Breast cancer knowledge and attitudes among women in Armenia

Background: Breast cancer, the most common invasive cancer among women, has high incidence and mortality rates among women in the Republic of Armenia. Advanced stage at detection limits treatment options and contributes to high morbidity and mortality. Understanding women's breast cancer knowledge and attitudes is important to developing targeted intervention programs addressing this major public health concern. Methods: A cross-sectional knowledge, attitudes, and practices (KAP) study was performed with 229 women attending regional outpatient clinics in the Republic of Armenia over the two-week period of June 19 to July 4, 2012. Data was collected from women ages 18-70 using a standardized survey administered in face-to-face intercept interviews. Results: Eighty-nine percent of women in Armenia accurately indicated that breast cancer was the most common cancer in women. Over 70% of women surveyed understood advanced age and smoking as potential risk factors, although the consensus was lower concerning other potential risk factors. Knowledge concerning signs and symptoms ranged between 60-80%. A majority of women (92%) understood that early diagnosis of breast cancer improves treatment outcome, although women's attitude towards breast cancer susceptibility was downplayed. With the exception of breast cancer endangering their marriage, the perceived seriousness was generally high. Conclusions: A majority of women surveyed in the Republic of Armenia acknowledged that breast cancer is the most common cancer among women. Overall knowledge levels were high and attitudes towards treatment positive. Public awareness campaigns targeting demographics with knowledge or attitude disparities may prove efficacious in increasing early detection of breast cancer and improving mortality due to breast cancer.

BREAST CANCER KNOWLEDGE AND ATTITUDES AMONG WOMEN IN ARMENIA by Kyle Simonsen A Senior Honors Thesis Submitted to the Faculty of The University of Utah In Partial Fulfillment of the Requirements for the Honors Degree in Bachelor of Science In Chemistry Approved: Dr. JHripsime Z. Wright Dr. Cynthia J. Burrows Supervisor Chair, Department of Chemistry Dr. Thomas Richmond Department Honors Advisor Dean, Honors College July 2013 ABSTRACT Background: Breast cancer, the most common invasive cancer among women, has high incidence and mortality rates among women in the Republic of Armenia. Advanced stage at detection limits treatment options and contributes to high morbidity and mortality. Understanding women's breast cancer knowledge and attitudes is important to developing targeted intervention programs addressing this major public health concern. Methods: A cross-sectional knowledge, attitudes, and practices (KAP) study was performed with 229 women attending regional outpatient clinics in the Republic of Armenia over the two-week period of June 19 to July 4, 2012. Data was collected from women ages 18-70 using a standardized survey administered in face-to-face intercept interviews. Results: Eighty-nine percent of women in Armenia accurately indicated that breast cancer was the most common cancer in women. Over 70% of women surveyed understood advanced age and smoking as potential risk factors, although the consensus was lower concerning other potential risk factors. Knowledge concerning signs and symptoms ranged between 60-80%. A majority of women (92%) understood that early diagnosis of breast cancer improves treatment outcome, although women's attitude towards breast cancer susceptibility was downplayed. With the exception of breast cancer endangering their marriage, the perceived seriousness was generally high. Conclusions: A majority of women surveyed in the Republic of Armenia acknowledged that breast cancer is the most common cancer among women. Overall knowledge levels were high and attitudes towards treatment positive. Public awareness campaigns targeting demographics with knowledge or attitude disparities may prove efficacious in increasing early detection of breast cancer and improving mortality due to breast cancer. TABLE OF CONTENTS ABSTRACT ii INTRODUCTION 1 BIOCHEMISTRY OF BREAST CANCER 1 BACKGROUND 20 METHODS 26 RESULTS 28 DISCUSSION 29 CONCLUSIONS 32 REFERENCES 33 iv INTRODUCTION The most common cancer among women, breast cancer poses a significant public health challenge especially in developing countries. In 2008, breast cancer had an incidence rate of 38.9 per 100,000, mortality rate of 12.4 per 100,000 and was responsible for 458,503 deaths globally (GLOBOCAN 2008,2013). Low and middle resource countries account for 45% of breast cancer cases and 54% of deaths (Anderson, et al., 208). The Republic of Armenia, while experiencing a high rate of literacy and moderate development, consistently ranks among the highest nations for age standardized mortality risk. Breast cancer accounts for 26% of cancers and 20% of cancer-related deaths among women in Armenia (GLOBOCAN 2008, 2013). Barriers to care, including late detection, contribute to this high rate in Armenia and other resource-limited nations. This study focused on quantifying knowledge and attitudes among women in Armenia to better understand these barriers. In addition, a brief review concerning the biochemistry of breast cancer will be presented. BIOCHEMISTRY OF BREAST CANCER Breast Cancer is a disease characterized by malignant cells within the tissues of the breast. It is typically classified as one of three distinct forms: ductal carcinoma, lobular carcinoma, and inflammatory breast cancer. The first type, ductal carcinoma, begins in the ducts which carry milk from the lobes of the breast to the nipple. Lobular carcinoma originates in the lobes of the breast where milk is produced. The third and least common, inflammatory breast cancer, presents as warm, red, and swollen breasts (General Information About Breast Cancer, 2013). As cancer begins from a handful of cell and invades surrounding tissue as it progresses, it is typically described by five stages which correspond to the seriousness. The first of these stages, stage 0, is known as breast cancer in situ. This stage of breast cancer is characterized by abnormal cells found within either the ducts or the lobes and designated as ductal carcinoma in situ and lobular carcinoma in situ respectively. These abnormal cells are non-invasive, meaning they have not spread into other tissue. There is little indication whether ductal carcinoma in situ may become invasive or not, and lobular carcinoma in situ rarely becomes invasive. Once stage I is reached, cancer has formed. Depending on certain factors, stage I is classified as either stage IA or stage IB. In stage I A, the mass of abnormal cells, or tumor, has grown to at most two centimeters but has not spread beyond the tissue of the breast. In stage IB, small clusters of breast cancer cells have spread to the lymph nodes. Stage IB can either present without any tumor in the breast or with a breast tumor of at most two centimeters. Stage II is again classified as either stage IIA or stage IIB. If the cancer is found in one to three axillary lymph nodes and no breast tumor or a tumor two centimeters or smaller is found, the cancer is described as IIA. If there is no spreading to lymph nodes, but the tumor is between two and five centimeters, it is also classified as IIA. Stage IIB can present as a tumor larger than five centimeters without spreading to lymph nodes. If the tumor is between two and five centimeters and is characterized by clusters of cancer cells in lymph nodes or has spread to one to three axillary lymph nodes, it is also considered stage IIB. 2 Stage III cancer is further classified as either stage III A, IIIB, or IIIC. In all three stages, the cancer has spread to lymph nodes in varying degrees. In stage III A cancer, one of three forms is present: Cancer is found in four to nine axillary lymph nodes with or without a breast tumor of any size, a breast tumor larger than five centimeters with small clusters of breast cancer cells in the lymph nodes, or a breast tumor larger than five centimeters with cancer found in one to three axillary lymph nodes. Stage IIIB is characterized by a tumor of any size that has reached the chest wall or the outer skin of the breast and caused swelling or formed an ulcer. The cancer may have spread to up to nine axillary lymph nodes. Stage IIIC breast cancer may have no tumor or a tumor of any size, but is primarily characterized by its spread to lymph nodes. This includes spreading to 10 or more axillary lymph nodes, lymph nodes above or below the collarbone, or axillary lymph nodes and lymph nodes near the breastbone. By the time breast cancer has reached stage IV, the cancer has spread to other organs in the body. Cancer often spreads to other parts of the body as cancer cells develop in the lymph nodes, which are then easily transported to other organs in the body. Up until Stage IV, the cancer is isolated in the tissue of origin and the nearby lymph nodes. From the lymph nodes, breast cancer typically spreads to the bones, lungs, liver, or the brain. Due to the advanced and delocalized nature of stage IV cancer, treatment options are more limited (Stages of Breast Cancer, 2013) (Singletary, et al., 2002). \ Cancer arises from disturbances of the highly regulated process of cellular division. All cells, from protozoans to white blood cells, rely on a highly complex balance between cellular division and apoptosis. Many cells in the body are replaced 3 frequently, such as white blood cells. Others, including skin cells, die less frequently and are replaced every few weeks. If the regulatory processes responsible for maintaining this balance become defective, cancer may arise (Nelson & Cox, Oncogenes, Tumor Suppressor Genes, and Programmed Cell Death, 2008). First, consider the highly regulated process of cellular division. The process of cellular division is typically described by four stages, known as Gi, S, G2, and M. Both G phases are considered gap phases where the cell performs its usual functions including normal growth. During the S phase, DNA replication takes place in preparation for cellular division, which occurs in the M, or Mitotic phase. Non­dividing cells are often considered "stalled" in an extended Gi phase indicated by Go. Depending on the cell type (such as white blood or skin cells), the length of these phases differ and is tightly controlled by regulatory proteins (Krogh, 2005). Two classes of regulatory proteins are important in guiding a cell through its cycle. These proteins signal when to move from one stage to another or prevent progression if the circumstances aren't favorable for division. Proteins from these families, cyclin and cyclin-dependent protein kinase (CDK), form a heterodimer, with cyclin acting as a regulatory subunit and the CDK as the catalytic subunit. In the absence of cyclin, the CDK subunit is essentially inactive. Cells maintain tight control over the activity of cyclins and CDKs, and each individual cyclin and CDK is highly susceptible to changes in the cellular environment. Growth factors, abnormalities in DNA replication, and a host of other signals can influence the activity of these proteins (Nelson & Cox, Regulation of the Cell Cycle by Protein Kinases, 2008). Researchers have discovered connections between expression of certain cyclins and stages of the cell cycle. For example, Cyclin D is highly expressed in the GO and G1 phases, Cyclin E in the G1 and S phases, Cylin A in the S phase, and Cyclin B in the G2 and M phases (Satyanarayana & Kaldis, 2009) (Nelson & Cox, Regulation of the Cell Cycle by Protein Kinases, 2008). As various cellular signals initiate expression of each cyclin, the cell cycle moves through the specific phases associated with each cyclin. As mentioned previously, cyclins have no catalytic function; they act primarily as binding partners with proteins from the CDK family. While the cell cycle is sensitive to concentrations of each cyclin, complete knockout of these molecules does not result in immediate cell cycle disruption. Mammalian cells maintain redundancies of cyclins, alternate proteins with nearly identical functionality. There are at least three variations of Cyclin D and B and two of Cyclin E and A. In addition, if the complete set of each cyclin is removed, the other sets may compensate for the missing functionality (Satyanarayana & Kaldis, 2009). Thus, even in a tightly controlled system, cells have developed fail-safe mechanisms to protect against cell cycle disruption. Similar connections have been located in the CDK family. CDK proteins are completely inactive unless bound by their specific cyclin partner. Upon cyclin binding, a critical residue becomes accessible for the CDK catalytic functions. The effect of cyclin on CDK activity is remarkable: cyclin binding increases the catalytic functions of CDK 10,000-fold. And while cyclin's primary function is to bind to CDK and activate its catalytic functions, CDK acts on a wide variety of other proteins. CDK acts through phosphorylating critical proteins, including lamins, myosin, and the retinoblastoma protein (pRb). Lamins are intermediate filaments in the nuclear envelope. Phosphorylation of these filaments aids in breakdown of the nucleus to allow segregation of chromosomes. Myosin is involved in the contractile machinery that separates daughter cells during cytokinesis. Finally, pRb is involved in an important regulatory system that detects DNA damage. If damage is found, pRb assists in arresting the cell cycle to prevent proliferation of compromised genetic material (Nelson & Cox, Regulation of the Cell Cycle by Protein Kinases, 2008). Similar fail-safe mechanisms have been found in CDK. There are more than 20 individual CDK proteins, and while their specific functions are still being studied, research has shown that many have multiple cyclin binding partners. For example, CDK1 is able to bind to cyclins Al, A2, Bl, and B2. However, CDK2 is also able to bind to cyclins Al and A2 in addition to B3, El, and E2. If CDK1 is missing, CDK2 can compensate by binding to Al and A2. Despite the inherent redundancies, failure of some cyclins or CDKs is known to cause defects or even lethality in mice. For example, complete deletion of Cyclin El produces fertile offspring with no abnormalities. Deletion of Cyclin Al produces viable offspring with no abnormalities, but the males are sterile. Deletion of CDK5, however, produces offspring with severe neurological defects which die immediately after birth. The right combination of these abnormalities on the cellular level could result in development of cancer. Therefore, understanding of the role of individual cyclin and CDK molecules is an active area of current research (Satyanarayana & Kaldis, 2009). Cells strike a delicate balance between proliferation and programmed cell death. Consider now the process of programmed cell death, or apoptosis. To counteract the rate of division, older or more worn out cells are destroyed. Under certain conditions, such as trauma, toxins, or lack of oxygen, cells undergo necrosis. Necrotic cells are damaged and unable to perform necessary functions. They swell and eventually burst, releasing harmful enzymes which may damage nearby cells. Under more favorable conditions, apoptosis occurs. Controlled by numerous signals, apoptosis ensures cell death minimizes damage to adjacent cells. A normal cell receives contradicting signals, some indicating to live and others indicating to die. When the signals to undergo programmed cell death win, apoptosis occurs. In contrast to necrosis, harmful enzymes are inactivated and cellular parts separated to be used by nearby cells (Silverthorn, Apoptosis Is a Tidy Form of Cell Death, 2010). There are two main pathways which lead a cell to commit suicide: a stress pathway and a death-receptor pathway. The stress pathway is triggered by intracellular proteins that cause the cell to die in response to factors such as viral infection, heat, hyperosmolarity, UV damage, and gamma irradiation. In relies primarly on internal signals. The death-receptor pathway is a response to extracellular signals such as the tumor necrosis factor (TNF) produced by the nervous system. When bound to specific TNF receptors, this signals the cell to perform apoptosis (Croce, 2008), (Nelson & Cox, Oncogenes, Tumor Suppressor Genes, and Programmed Cell Death, 2008). Dysfunction of membrane-associated signal receptors, including the TNF receptor, is among the numerous cellular disruptions that can lead to breast cancer. Diagnostics of the specific disruption are often used to determine an appropriate treatment regimen (Patani, Martin, & Dowsett, 2013). Unicellular organisms respond to environmental variables to dictate their actions. For example, if nutrients are sensed, the cell will respond to the stimuli by moving towards the source. Multicellular organisms, however, rely on a complex system of extracellular signaling to coordinate their behavior. The body's endocrine system is primarily responsible for excreting hormones which dictate much of this action. These hormones act as signal molecules, traveling throughout the body and eliciting a response at their target cells. In this way, the body maintains control over its vast collection of diversified cells. Signal molecules such as hormones elicit a response by one of two ways. In the genomic mechanism, signal molecules travel through the cell membrane and enter the nucleus. The signal then binds to the target molecule, which typically regulates DNA transcription. In the non-genomic route, the signal molecule remains extracellular and relies on a process known as signal transduction. The general flow of the signal travels from the signal molecule through receptor molecules (typically membrane-associated proteins), intracellular signal molecules, and ends at the target molecule which causes the appropriate response. This elegant system ensures a rapid, sensitive, and accurate response to extracellular signals. While the genomic route may take hours to create a response, the non-genomic mechanism can act within seconds (Silverthorn, Communication, Integration, and Homeostasis, 2010). Receptor proteins associated with the membrane are typically highly specialized. Their active sites recognize only a select set of molecules which bind to key amino acid residues. The four main categories of membrane proteins are receptor-channels, receptor-enzymes, G protein-coupled receptors, and integrin receptors. The binding of the appropriate ligand causes each of the protein complexes to activate a secondary response, such as opening an ion channel or activating an intracellular enzyme. Protein receptors play a significant role in medicine; roughly half of current pharmaceuticals act on receptor molecules. After recognition by the receptor molecule, a secondary response is created. This secondary response has two key steps: amplification and transduction. Transduction is the process whereby the signal is transformed into another form. The final signal rarely bares any resemblance to the initial signal. Before the final signal is produced, the form may change several times. The other step is amplification of the signal. Within the cellular soup, a single signal is apt to be lost; a million signals are likely to reach their mark. Therefore, cells use the activity of kinases and other enzymes to cause a many-fold increase in signals known as enzymatic cascades. The process begins at the receptor molecule where the initial stimulus actives an enzymatic process. The product from that process activates yet another enzymatic process, and it continues down the cascade until the final signal molecule is produced. If the primary receptor molecule acts on ten molecules every second, and each additional step proceeds at the same rate, a five-step cascade could produce hundreds of thousands of cellular signals within seconds. This process explains why genomic response mechanisms take hours, while non-genomic responses occur in as little as seconds. Signal transduction minimizes the diffusion rate barrier by saturating the cell with signals (Silverthorn, Communication, Integration, and Homeostasis, 2010). Understanding the disruptions of these and other cellular processes is key to preventing and curing breast cancer. The severity of breast cancer is highly related to the specific abnormalities. Much research is dedicated to identifying the specific aberrations which result in carcinogenesis. Among the identified abnormalities are hormone receptor malfunctions. Three key hormone receptors have been linked to breast cancer development: estrogen receptor alpha (ERa), progesterone receptor (PR), and the human 9 epidermal growth factor receptor 2 (HER2). Analysis of the status of these receptors is common to better understand the form of breast cancer, thus allowing more personalized treatments. In addition to these three receptors, other biomarkers are being discovered which will greatly improve specialized breast cancer treatment (Patani, Martin, & Dowsett, 2013). The primary purpose of the ERa receptor is to detect estrogen, an important regulatory hormone. Due to its influence in many physiological processes, it has been connected to many diseases. These include many forms of cancer, osteoporosis, neurodegenerative diseases, cardiovascular disease, diabetes, and obesity. Estrogen receptors (ERs) are located in both the nucleus and membranes of cells and are responsible for transcription regulation. Similar to most signals, estrogen may take either a genomic route or a nongenomic route. In the genomic route, estrogen molecules diffuse through the cell membrane and work their way to the nucleus, where they bind to ERs and stimulate formation of a multi-protein regulatory complex. This response may occur over several hours. The faster route, the nongenomic route, relies on ERs located at the cell membrane. This mechanism activates more nonspecific cellular responses including activation of kinases or increased levels of Ca2+ and NO (Deroo & Korach, 2006). As 60-70% of breast cancers are ERa-positive, meaning overexpression of the ERa gene, it is a significant target for treatment (Mohibi, Mirza, Band, & Band, 2011). Two predominant theories exist concerning high exposure to estrogen and cancer. As binding of estrogen to ERs increases proliferation of mammary cells, the elevated rate of cellular division increases the risk for replication errors. These errors could have detrimental effects on cellular processes such as apoptosis, proliferation, or DNA repair. 10 The second theory states that the byproducts of estrogen metabolism damage DNA directly. These mutations then cause the same detrimental effects as above. When treating ERa-positive cancers, usage of endocrine therapies to inhibit ERa activity such as the drugs tamoxifen and raloxifen is efficacious. These compounds act as selective estrogen receptor modulators (SERMs) and have selective agonistic and antagonistic effects on estrogen receptors. These drugs mimic the structure of wild type estrogen and bind to estrogen receptors. In the breast, they act as antagonists, blocking estrogen binding to suppress the normal estrogen response (Deroo & Korach, 2006). Expression of progesterone receptors is highly linked to activity of the ERa receptors. Among the transcriptional targets of ERa is the gene PGR which is responsible for synthesis of the progesterone receptor (PR). In common with other steroid receptor molecules, it contains a hormone binding domain and a DNA binding domain (Roemer, et al., 2006). Upon binding of progesterone, its transcription regulation activity is stimulated. Despite its close relationship to ERa, diagnostic of PR alone contributes little towards informed breast cancer treatment (Patani, Martin, & Dowsett, 2013). The third common histological marker is the human epidermal growth factor receptor 2 (HER2). Overexpression of this marker is found in approximately 15% of breast cancer cases, of which half are ERa-negative. While the exact mechanism is not well characterized, amplification of HER2 typically results in poor prognosis. Among the pharmaceuticals used for treatment are trastuzumab and lapatinib (Patani, Martin, & Dowsett, 2013). More recent microscopy studies have shown that HER2 proteins form clusters in the cell membrane that may increase the risk of breast cancer (Nagy, et al., 1999) (Kaufmann, Muller, Hildenbrand, Hausmann, & Cremer, 2011). These three biomarkers are used to determine they phenotype of common breast cancer. Most forms of breast cancer can by classified as one of three immunophenotypes: ERa-positive, ERa-negative/HER2-positive, and ERa-negative/HER2-negative (i.e. triple negative). Clinical oncologists utilize these immunophenotypes to make informed decisions when developing treatment plans. In addition to these three common markers, Ki67, cyclin D l, cyclin E, estrogen receptor beta, topoisomerase Ila, Urokinase-type plasminogen activator and inhibitor, circulating and disseminated tumor cells, tumor-specific DNA, and clinical tumor markers have all been suggested as potential biomarkers for diagnosing breast cancer and developing individualized treatment regimens (Patani, Martin, & Dowsett, 2013). Among the most well documented causes of cancer are the activation of oncogenes and the inactivation of tumor suppressor genes. The proteins and RNA encoded by these genes are important in the regulation of the cell cycle. As cancer is typically described as unregulated cellular growth, disruption of cell cycle regulation is alarming. Oncogenes, known as proto-oncogenes before aberrations, often code for proteins and RNA necessary for the natural growth and division of cells. They are not, therefore, intrinsically bad. It is when they become mutated or overexpressed that cancer begins to develop (Nelson & Cox, Oncogenes, Tumor Suppressor Genes, and Programmed Cell Death, 2008). There are six broad categories of products oncogenes code for; transcription factors, chromatin remodelers, growth factors, growth factor receptors, signal transducers, and apoptosis regulators. Transcription factors regulate the level of expression of specific genes and thus their respective proteins. Mutations in the genes for 13 transcription factors affect the protein composition of the cell have been shown to increase expression of many cell division control genes (Croce, 2008). Chromatin plays an important role in the packaging of DNA. Chromatin is composed of DNA wrapped around protein complexes called nucleosomes, which are made up of eight histone subunits. Tightly packed chromatin is transcriptionally silent. To activate these genes, the chromatin must be remodeled in one of two ways. The first requires ATP-dependent enzymes to physically move the nucleosomes. The second relies on enzymes which modify the histone tails. The epigenetic code on the histone tails greatly affects how they interact with other chromatin-associated proteins. Rouge chromatin remodeling machinery could potentially increase expression of cancer-causing oncogenes and decrease expression of cancer-fighting tumor suppressor genes (Nelson & Cox, Oncogenes, Tumor Suppressor Genes, and Programmed Cell Death, 2008). For example, research has shown that fusion of the chromatin remodeling complex ALL1 with one of 50 proteins disrupts its normal function (Croce, 2008). Growth factors are released to stimulate proliferation of various cell types. For example, during blood coagulation and wound healing, these signals are important to help the body recover properly. There are several well documented examples of dysfunctional growth factors which lead to tumor growth. Overexpression of platelet-derived growth factor (PDGF) induces unregulated cell growth, and inactivating mutations in the APC protein result in free P-catenin which leads to cell proliferation and invasion (Croce, 2008). In addition to growth factor aberrations, the membrane-associated growth factor receptors may become mutated. The previously discussed ERa, PR, and HER2 disruptions belong to this category. Another form of dysfunction is the loss of a ligand binding site resulting in constant activation of the receptor molecule. A common breast cancer disruption is in the epidermal growth factor receptor (EGFR). The normally functioning EGFR is a transmembrane receptor protein that recognizes the epidermal growth factor (EGF) molecule. Upon EGF binding, the tyrosine kinase domain is activated, resulting in signal transduction. The oncoprotein form, ErbB, is identical to the normal receptor except for missing the EGF binding site. It is thought that this oncoprotein is a result of a truncated form of the normal EGFR gene which is missing the extracellular EGF receptor. As a result, the ErbB protein is constantly active and sends the signal to divide even in the absence of EGF (Nelson & Cox, Oncogenes, Tumor Suppressor Genes, and Programmed Cell Death, 2008). Oncogenic mutations in signal transduction pathways are similar to those found in growth factor receptors. The two classes of proteins greatly affected by this type of oncogene are nonreceptor protein kinases and guanosine-triphosphate-binding proteins. If an activating mutation is caused in a protein involved in signal transduction, the regulatory portions of the protein fail to activate or deactivate the enzymatic sites. Most signal transduction proteins rely on phosphorylation or dephosphorylation to regulate enzymatic activity. If an activating mutation occurs, the signal is sent even without the necessary stimuli. Common mutations in signal transduction occur in PI3K, AKT, and SGK, all of which are important in tyrosine kinase signaling (Croce, 2008). The final class of oncogenes, apoptosis regulators, inhibit programmed cell death when mutated. As mentioned above, apoptosis is a highly regulated process. When this regulatory machinery is disrupted, damaged cells proliferate rather than die. In many cancer cells, the apoptosis-inhibiting protein BCL2 is highly expressed. This prevents the cell from performing stress-induced apoptosis. In the death-receptor apoptosis pathway, binding by the ligands Fas, TRAIL, and tumor necrosis factor a are necessary to causing cell death (Croce, 2008). Any disruption of these death-factors or their respective receptors could contribute to proliferation of aberrant cells. The presence of these proto-oncogenes is not sufficient, however, to cause cancer. These proto-oncogenes must become activated through chromosomal rearrangements, mutations, or gene amplification. In chromosomal rearrangements, the transcription of the oncogene increases or becomes deregulated. This occurs through translocations and inversions, however such modifications are considerably rare in breast cancer (Croce, 2008). Mutations are defined as permanent changes to the DNA nucleotide sequence. In a typical day, many thousands of mutations may occur, but due to the highly effective system of DNA repair, only 1 in every 1,000 mutation is permanent. Given that only around 30% of human DNA consist of genes and only 1.5% are expressed in proteins (Nelson & Cox, Genes and Chromosomes, 2008), much of these mutations go unnoticed. If they do fall within a coding region of DNA, many will be silent, either not changing the amino acid sequence or changing a non-essential amino acid (Nelson & Cox, DNA Metabolism, 2008). The negative effects of DNA mutations are seen when they do alter the behavior of a protein or change the way it is expressed. Among the many ways DNA may become damaged are deamination, hydrolysis of the Ar-/?-glycosyl bond, UV-induced pyrimidine dimerization, ring opening and fragmentation due to ionizing radiation, 15 oxidative damage from hydroxyl radicals, and damage from other carcinogenic compounds (Nelson & Cox, Nucleic Acid Chemistry, 2008). Standing in opposition to oncogenes are tumor suppressor genes. When acting correctly, they restrain cellular division and prevent uncontrolled growth. The cell is kept in constant check between these two contradicting signals. Only when conditions are precise is the cell allowed the progress through the cell cycle and divide. Built into tumor suppressor genes is a fail-safe mechanism. Mutations in oncogenes are typically dominant-only one mutated copies in the genome is required to send the signal to divide. The opposite is true for tumor suppressor genes. A defect in these genes is recessive. Both copies of the gene must become corrupted to lose the tumor suppressing effect. As most forms of cancer require mutations in both oncogenes and tumor suppressor gene, such a mechanism provides reasonable defense. Examples of tumor suppressor genes include pRb, p53, p21, and the breast cancer genes BRCA1 and BRCA2 (Nelson & Cox, Oncogenes, Tumor Suppressor Genes, and Programmed Cell Death, 2008). Mutations in the tumor suppressor gene p53 have been found in about 50% of all human cancers (Nelson & Cox, Oncogenes, Tumor Suppressor Genes, and Programmed Cell Death, 2008) (Hollstein, Sidransky, Yogelstein, & Harris, 1991). P53 is critical to the cellular response to stress, initiating apoptosis, DNA repair, cell cycle arrest, and metabolic homeostasis maintenance in response to signals such as deregulation of oncogenes, DNA damage, metabolic depravation, and telomere shortening. In addition to its critical role in cellular decision making, it is also highly mutated, more than any other human tumor suppresser gene overall and in around 23% of breast cancers. Among the effects p53 has upon tumorigenesis include signaling pathway disruption, genomic instability, reduced sensitivity to apoptosis signals, and affected cellular senescence. Because of its long list of binding partners, mutations in p53 can be debilitating to the cell's natural tumor defenses (Walerych, Napoli, Collavin, & Del Sal, 2012). The tumor suppressor genes BRCA1 and BRCA2 have been shown to have a significant link to breast cancer. Although only 5% of breast cancer cases are known to have a familial link, understanding the underpinnings of the genetic disposition is important to preventing cancer. These two tumor suppressor genes have important roles in DNA repair, transcriptional response to DNA damage, and cell cycle arrest due to DNA damage. Their known binding partners are extensive. BRCA1, for example, is known to interact with 10 proteins involved in DNA repair, 14 in transcription regulation, five in cell cycle control, and four others. Mutation in such a critical set of proteins puts individuals at a high risk for breast cancer as well as increased susceptibility toward ovarian, pancreatic, prostatic, and male breast cancers (Yoshia & Miki, 2004). The role of BRCA1 and BRCA2 in cell cycle arrest is particularly interesting. As mentioned above, regulation of the cell cycle is important to prevent damaged cells from propagating. Many proteins, including BRCA1 and BRCA2, are involved in repairing DNA and maintaining correct transcription of DNA, but if these systems fail, the ultimate checkpoint is at the junction between the G2 phase and the M, or mitotic phase. Once a cell passes this threshold, the cell will divide and DNA, damaged or not, will be carried on to the next generation. Resent research has shown that the proteins ataxia telangiectasia mutated (ATM) and BRCA1 are necessary for successful regulation of the G2/M-phase checkpoint. It has been suggested that ATM phosphorylation of BRCA1 in 17 response to DNA damage is critical for cell cycle arrest. Furthermore, BRCA1 mutations which remove phosphorylation abilities are also defective in cell cycle arrest. BRCA1 also interacts with the tumor suppressor gene p53 described above. BRCA1 co-activates p5 3-mediated gene transcription, which produces proteins responsible for cellular response to stress, apoptosis initiation, DNA repair, cell cycle arrest, and metabolic homeostasis maintenance. In particular, BRCA1-deficient cells have low expression of the p53-transcribed gene 14-3-3a, a major checkpoint control gene (Yoshia & Miki, 2004). In addition to the genetic factors involved, the growing field of epigenetics is likely to influence breast cancer diagnosis and treatment. While traditional genetics focuses on the four-letter genetic code of DNA, epigenetics studies the changes in gene expression due to mechanisms other than the four-letter DNA code. This area of research has exploded in the past several years and may provide insights into breast cancer. Based on the Greek root -epi, meaning over or above, epigenetic modifications provide another level of information contained within our DNA. While the full purpose of such modifications are yet unknown, epigenetics may shed light on the purpose of genetic material not transcribed into useful proteins. One role may include regulation of gene expression. Given the massive amount of DNA in the nucleus, cells have developed novel techniques to ensure only genes coding for necessary elements are accessible to transcription machinery. Additionally, cells are adept at ensuring that only necessary genes are transcribed at the correct levels at the correct time. Those genes that are actively transcribed are relatively accessible, while unnecessary DNA is packaged tightly in complex levels of organization, including chromatin as discussed above. The tighter 18 the packaging, the less accessible genes are to transcription machinery, thus altering their expression level. One purpose of epigenetic modification could be as an indication for chromatin remodeling machinery to compact or loosen DNA packaging. Current epigenetic research seeks to understand and characterize the epigenetic markers and the protein complexes which interact with them. One key epigenetic marker is methylation of the DNA nucleotide cytosine. This modification is recognized by several proteins that bind DNA. There are currently three identified families of these methyl-CpG binding proteins (MBPs): the MBD family, the SRA family, and the Zinc Finger family. Each MBP has a unique binding motif for methylated DNA within various preferred contexts. Within the zinc finger family are the proteins kaiso, ZBTB4, ZBTB38, and the more recently discovered ZFP57. The protein kaiso has two modes of recognition. It binds a consensus sequence known as the kaiso binding site (KBS) as well as the modified base 5-methylcytosine within the context of CpG dinucleotides. The structure features three modified Cys2His2 zinc fingers which interact with nucleotides in the DNA major groove. Zinc finger two adopts a traditional P(3a fold, while zinc finger one adopts a PPPa fold, and zinc finger two a ppap fold. Both the C and N terminal extensions interact with the DNA and provide stability for the binding. A common characteristic within the zinc finger family of MBPs are inclusion of a zinc finger binding domain and a protein-protein interaction domain. Kaiso, ZBTB4, and ZBTB38 feature BTB/POZ domains, while ZFP57 contains a KRAB domain, both linked to transcription repression machinery. Research has shown the regions rich in methylated CpG dinucleotides are more tightly packaged, suggesting that these zinc finger binding proteins recruit chromatin remodeling machinery and restrict expression of the associated genes. (Buck- Koehntop & Defossez, 2013). This new field of epigenetics is likely to change current perspectives on countless diseases such as breast cancer. Understanding the biochemical underpinnings of this disease will enable more effective and efficient approaches to diagnosis and treatment. These discoveries along with innovation in medical practice and public health will prove efficacious in reducing the global burden due to breast cancer. BACKGROUND Armenia is a former Soviet Republic located north of Iran and east of Turkey with a population of 2.9 million. It has a highly homogenous population, with 98% identifying as ethnically Armenian, and 99% identifying as Christian, primarily Armenian Apostolic. Their basic infrastructure is highly developed, including sanitation, education, and healthcare. Nearly 100% of their population above the age of 15 is literate, 98% have access to improved water sources, and their average life expectancy is 74 years (CIA - The World Factbook, 2013). Armenia's age standardized rates for breast cancer indicate a moderate incidence rate and high mortality rate, both regionally and globally. In the 2008 IARC study, Armenia had a yearly incidence rate of 47.3 per 100,000 and mortality rate of 25 per 100,000 women. As stated previously, the global average age standardized rates were 38.9 and 12.4 per 100,000. Armenia's most culturally and geographically similar neighbor Georgia had age standardized rates of 38.5 and 19.7 per 100,000 respectively (GLOBOCAN 2008, 2013). These data indicate a strong disparity between age standardized incidence and mortality rates. The major public health concern demands 20 21 significant financial resources and greatly affects the quality of life of women in Armenia. In addition to indicating a major public health concern, these high rates also emphasize other disparities faced by women in Armenia and similar nations. If women are perceived to be and feel powerless, it is likely to affect their response to breast cancer prevention efforts. The 2010 Armenia Demographic and Health Survey (ADHS) measured women's empowerment by their influence in family and personal decisions and men and women's perspectives on spousal abuse. The report states that [t]he study of women's status and empowerment-important in its own right- takes on special significance in study of demographic and health outcomes. As caretakers for their children, women are the direct or indirect targets of many population, health, and nutrition programs. The constraints that women face while they learn to access, and utilize these and other developmental programs are inherently tied to their status in society as well as in the home. Women's knowledge and attitudes towards health have a profound effect upon their children. Based on the 2010 ADHS, women take a prominent role in decision making, including spending of the husband's income. This was consistent for both urban and rural families (National Statistical Service [Armenia], 2012). With respect to spousal abuse, 9.3% of women indicated at least one justified reason for a husband to strike or beat her. That number jumps to a startling 19.9% when men were asked the same question. In rural settings, 28.4% of men indicated at least one reason that justified hitting or beating their wife (National Statistical Service [Armenia], 2012). The Armenian government has introduced aggressive awareness campaigns aimed at addressing this problem. These have included advertisements in public places and an establishment of a telephone hotline. The efficacy of such programs remains to be seen, but if these statistics are a reasonable indication of women's empowerment, rural regions may prove attractive targets for awareness programs. The ability of the healthcare system in Armenia to detect and treat breast cancer has been augmented through the efforts of non-governmental and private organizations. For example, the Armenian-American Wellness Center, funded by a United States-based non-profit organization, specializes in breast cancer screenings. In 2009, the center performed over 14,000 screenings and focuses on making mammography screenings more widely available through outreach programs (Accomplishments - Healthier Nation, 2013). Despite the availability of such services, the high cost of breast cancer treatment remains a significant issue. With an average monthly family income of $294 (National statistical service: average nominal monthly salary in Armenia reaches 119, 791 in November 2012, 2013), financial resources remain a substantial barrier. While the understanding of specific causes of breast cancer is limited, several risk factors have been shown to increase the risk of developing breast cancer. Increased age, a family history of breast cancer, and genetic factors heighten the higher risk of developing breast cancer. Other factors that may contribute include alcohol use, smoking, childbirth factors, obesity, radiation exposure, and exposure to certain chemicals. Misconceptions regarding breast cancer risk factors include the impact of breast implants, antiperspirant usage, and wearing underwire bras, all of which do not raise breast cancer risk. Established symptoms include breast lumps, breast and nipple changes, and nipple discharge (Breast cancer - PubMed Health, 2011). Without adequate public awareness of signs, symptoms, and early detection methods, the high mortality rates are unlikely to change. 22 In the effort to decrease mortality due to breast cancer in developing countries, public awareness and positive attitude are fundamental. Measuring the level of knowledge concerning and the attitude towards diseases such as breast cancer is a critical task of public health experts. To determine potential barriers and guide the implementation of intervention programs, Knowledge, Attitude, and Practice (KAP) studies are commonly used. Distinct from cross-sectional descriptive studies, KAP studies employ a smaller sample size and often require less time and fewer resources. While KAP studies lack the accuracy of more rigorous studies and are vulnerable to biases, they are effective at determining baseline information prior to more descriptive studies (The KAP survey model - Medecins du Monde, 2013). Due to accessibility, KAP studies are becoming increasingly utilized in resource-limited countries as pilot studies to obtain information regarding various health concerns such as breast cancer. A KAP study performed in Pakistan found a low level of knowledge despite an overall positive attitude. Performed in a country with a low average socioeconomic status, Pakistan is characterized by high incidence and mortality due to breast cancer. Based on these factors, the authors argue that to decrease mortality, early detection through breast cancer awareness is necessary. Conducted in a hospital among women with no signs or symptoms of breast cancer, the population demographics were characterized by 34.3% illiteracy, and were composed primarily of urban housewives. It was found that 82.9% of women interviewed were aware of breast cancer, with the remainder of the study focusing on this group. Interesting to note was that a majority of women's primary source of breast health information was friends, relatives, and neighbors; few women obtained their information from medical professionals. While 23 83% of those surveyed understood breast lumps as a symptom, less than 50% were aware of any other symptoms. Beyond average knowledge levels, "awareness significantly correlated with education status, urban residence, and monthly income." Despite the low knowledge, 94.7% said they would consult a doctor if a lump was found. Additionally, the attitude towards treatability correlated with education status and higher income. Knowledge of Breast cancer was deficient in the population, but the positive attitude suggests efficacy of awareness campaigns (Gilani, et al., 2010). Despite a small sample size, a Nepalese study showed similar results. A hospital-based KAP study determined an average knowledge score of 65% among participants, although 26% of those surveyed scored below fifty percent. Knowledge score correlated well with education, occupation, and breast cancer counseling during medical visits. While a majority of those surveyed understood that breast cancer typically presents as lumps, 60% were unaware of the painless nature of breast cancer or that it may occur without lumps. The researchers conclude that although knowledge score was positive, several major misconceptions persist. They suggest further counseling during medical visits and a greater awareness level among the general population to decrease mortality due to breast cancer. Understanding the correlation between physician counseling and patient knowledge is a critical step in addressing breast cancer (Bhatt, et al., 2011). A KAP study in Accra, Ghana found that study participants were poorly informed concerning breast cancer risk factors, signs, and symptoms although those with higher education were more knowledgeable. Attitudes were a significant factor, as many women cited religious or social barriers to care. The researchers assert that approaches used in more developed countries are not as efficacious in resource-limited countries. They 24 ]I suggest developing the "theory of planned behavior" for breast cancer education and j i awareness based on the specific culture of their population. Further use of identified : preferred media outlets is also suggested as a practical means to decrease the high mortality. This study points out the danger of approaching breast awareness without consideration of country-specific culture and values (Opoku, Benwell, & Yarney, 2012). In a thorough studied performed in Doha, Qatar, Shaikha and Salama identified relatively high levels of knowledge, especially compared to similar nations. A large number of those surveyed expressed fear towards breast cancer and its consequences, but a majority felt that it was not a hopeless disease. Interesting to note is the lack of perceived susceptibility, especially in the context of higher knowledge. Much as in other studies, it was determined that knowledge concerning breast cancer and prevention methods decreased with advancing age. The comprehensive approach taken in this study minimized biases and provides relatively accurate and precise data (Shaikha & Salama, 2011). Increased age is a well understood risk factor for developing breast cancer. However, increased age has been shown to correlate with a decreased awareness of breast cancer risk factors, signs, and symptoms. A study performed in Canada found that knowledge concerning breast cancer diminished with age and a similar trend was observed for attitude towards breast cancer. Remarkably, older women considered themselves less susceptible to breast cancer despite evidence to the contrary. They also were skeptical of the benefits of early detection (Mah & Bryant, 1992). Age as a factor for knowledge and attitudes presents a great barrier to intervention programs and should be addressed in awareness campaigns. 25 ; A number of major biases are inherent in many KAP studies such as those cited. As most are conducted in health centers, the data are not always broadly generalizable. For example, the Nepalese study cited an 80% literacy rate among those surveyed compared to a national average of 35% among women. The investigators point out this discrepancy and remark that results may differ for women from rural, poor education, or low socioeconomic backgrounds (Bhatt, et al., 2011). It is probable that urbanized women with a higher education and socioeconomic status are more likely to attend health centers. This may result in skewed data and must be taken into consideration when analyzing these studied. Care must be taken to avoid misrepresenting data through overgeneralization (The KAP survey model - Medecins du Monde, 2013). Despite their disadvantages, KAP studies are an important tool for quantifying public health concerns as organizations, both public and private, strive to improve global health. Resource-limited countries bear a significant disease burden especially due to breast cancer. Before breakthrough medical research finds application in these struggling systems, public awareness and informed attitudes are necessary foundations. Measurement and quantification of these variables guides targeted intervention programs aimed at decreasing mortality due to breast cancer. Combined with aggressive support from national policy makers, such movements will prove efficacious in decreasing mortality and improving the quality of life among women in Armenia and similar developing countries. METHODS Using a cross-sectional knowledge, attitudes, and practices survey adapted from a study performed in Qatar (Shaikha & Salama, 2011), 229 women in health centers within the Republic of Armenia were surveyed in face-to-face intercept interviews June 16-July 4, 2012. All study materials were granted institutional review board (IRB) approval by the University of Utah and the Republic of Armenia Ministry of Health. The survey population included women ages 18-70 attending regional outpatient clinics. All participants provided verbal consent to use de-identified information collected from the study. They were allowed to skip questions they felt uncomfortable answering and could prematurely end the survey at any time. All means were employed to protect the anonymity of respondents and instructions were provided if they wished to express any concerns related to the study. The KAP survey was divided into four sections: personal and demographic information, knowledge about breast cancer, attitudes towards breast cancer, and practice of breast self-examination. A total of 70 questions were administered utilizing multiple choice, yes/no/I don't know, likert scale, and open-ended questions. Questions relating to breast self-examination are not considered within the scope of this paper. Demographic information was collected through multiple choice questions with open ended questions relating to age and languages spoken. Questions concerning breast cancer knowledge utilized a yes/no/I don't know multiple choice format. Information concerning attitudes towards perceived seriousness and perceived susceptibility took the form of statements to which participants responded on a likert scale from one to five. One represented strongly disagree and five corresponded to strongly agree. All participants interviewed spoke Armenian, the national language of Armenia. This was a natural result of the population's homogeneity and not a sampling requirement. Interviewers without Armenian competency administered the surveys through an interpreter. To minimize biases, reasonable attempts were made to maintain privacy during the interview. Additionally, male interviewers were required to have a female interpreter or assistant present. Following data collection, coded answers were recorded electronically and paper surveys destroyed. Primary analysis was performed using Microsoft Excel software with more rigorous data analysis pending. RESULTS The sample included women who self-identified as urban and rural, married and unmarried, and from all age groups, household income levels, education levels, and occupation categories. 86% of women surveyed understood that breast cancer is the most common cancer among women. 7% felt that some other cancer was most common, and another 7% answered that they didn't know. 92% of women surveyed understood that early diagnosis improve treatment outcome with only 5% dissenting. Knowledge concerning potential breast cancer risk factors was generally high, although a number of misconceptions persisted. Among the established risk factors of smoking, advanced age, painless breast lump, and heredity, between 67-76% of women correctly identified the first three as risk factors. The role of family history of breast cancer was not well understood, despite strong scientific proof supporting it. Only 38% of respondents acknowledged an increase risk due to hereditary factors. Concerning breast cancer signs and symptoms, the overall knowledge was reasonably high. The study focused on five established signs and symptoms and asked women to indicate whether they were actual signs and symptoms. 80% indicated change in breast shape, 74% painless breast lump, 72% pain in the breast, 62% sore on or around 28 the nipple, and 61% nipple discharge. The percentages of "I don't know" responses ranged between 7% and 23%. In response to the 13 questions relating to perceived seriousness, 70% of respondents agreed with statements concerning breast cancer seriousness. 23% disagreed, with an average of 7% neither agreeing nor disagreeing with statements on breast cancer seriousness. The statement most identified with was "Problems I would experience from breast cancer would last a long time" followed by "If I had breast cancer my whole life would change." Interesting to note, however, was the average response to the statement, "Breast cancer would endanger my marriage." A majority of participants disagreed with this statement, indicating a high level of perceived fidelity among women. While the average perceived seriousness was generally high, perceived susceptibility was relatively low. Five statements relating to personal breast cancer susceptibility were read, and participants responded again on a scale of one to five on a likert scale. 27% of respondents agreed with these statements, while an average of 58% disagreed. 15% neither agreed nor disagreed. The statement most identified with was "I worry a lot about getting breast cancer" followed by "There is a good possibility that I will get breast cancer." While these statements were the most identified with, the mean answers were 2.82 and 2.59 respectively, indicating that on average, women disagreed with these statements. DISCUSSION Addressing mortality due to breast cancer among resource-limited nations including the Republic of Armenia is filled with complexity. Approaches taken in more-developed nations such as the United States and many European countries find little application in nations with more limited healthcare capacity. Furthermore, interventions are likely to fail without consideration of country-specific culture, values, political situation, and healthcare infrastructure. A one size fits all approach wastes precious time and resources and often impedes capacity building efforts in developing nations. The World Health Organization's recommendations on breast cancer state that "[rjaising general public awareness on the breast cancer problem and the mechanisms to control as well as advocating for appropriate policies and programmes are key strategies of population-based breast cancer control." Suitable healthcare policies and breast health awareness are essential components to a comprehensive breast cancer prevention plan. The results from this study will serve efficacious to inform national policy makers in developing targeted intervention programs addressing both public awareness and national programs. Overall knowledge levels were relatively high. While some misconceptions persisted among the population, general knowledge concerning the risk factors, signs, and symptoms was adequate. While awareness campaigns need not neglect knowledge factors, initial findings do not indicate a major problem. Perceived seriousness was generally high. It appeared women in Armenia comprehend the seriousness of breast cancer and its effect upon their lives. While a generally high perceived seriousness is helpful in prompting action, responses to some key statements require attention. The average response to the statement "breast cancer is a hopeless disease" was 3.02, indicating that women have a generally hopeless view of breast cancer. Responses to the perceived personal susceptibility statements indicate a general softening of breast cancer risk despite its high prevalence. Women who ignore the possibility of contracting breast cancer are less likely to take the necessary preventative measures including seeking early detection. As a practical mean to improve awareness and increase early detection, integrating breast cancer screening into the recommended yearly check-ups could prove useful. This would require both physician training and patient awareness. If such breast health checkups were made available through governmental programs, more women are likely to take advantage of them. Anecdotal evidence suggests that younger women in Armenia foster a more positive attitude towards treatment of breast cancer than the older generations. Due to the widespread availability of inexpensive social media outlets, targeting younger women to encourage their mothers and grandmothers to be checked may result in earlier detection rates. The results cited in this article represent preliminary data analysis. More rigorous studies, including correlation studies to understand specific demographics are required to draw further conclusions. It is vital to understand specifically which age groups, educational background, place of residence, and other groups have the greatest knowledge and attitude disparities. A greater understanding of these factors will better guide awareness campaigns. Based on the sampling method, a number of inherent biases are present, which limit the broad generalizability of this study. As participants were recruited through intercept interviews in hospitals, data may vary slightly for the larger population of women. Additionally, only cities in the northern portion of Armenia were visited due to the relative inaccessibility of the more rural southern regions. Response bias is common among studies of this nature and must also be taken into account. Despite these 31 limitations, this KAP study allowed a significant amount of quantitative data to be collected within the time and resource constraints of the project. It provides a foundation for future studies and contributes significantly to the resources available to public health efforts in Armenia. CONCLUSIONS A cross-sectional knowledge, attitudes, and practices (KAP) study was performed with 229 women attending regional outpatient clinics in the Republic of Armenia between June 19 and July 4,2012. Data was collected from women ages 18-70 using a standardized survey administered in face-to-face intercept interviews. A majority of women surveyed in the Republic of Armenia acknowledged that breast cancer is the most common cancer among women. Overall knowledge levels were moderate and attitudes towards treatment positive. Perceived seriousness was well understood, with perceived personal susceptibility downplayed. Public awareness campaigns targeting demographics with knowledge or attitude disparities may prove efficacious in increasing early detection of breast cancer and improving mortality rates. With an objective to foster more patient participation in the diagnosis and treatment of breast cancer, comprehensive breast cancer control programs will empower women in Armenia and improve their quality of life. 33 REFERENCES GLOBOCAN: Country Fast Stat. (2008). Retrieved January 7, 2013, from International Agency for Research of Cancer: http: / / globocan.iarc.fr/factsheets/populations / factsheet.asp?uno=900 Breast cancer - PubMed Health. (2011, December 14). Retrieved January 9, 2013, from PubMed Health: http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001911/ Accomplishments - Healthier Nation. (2013, April 4). Retrieved from healthiernation.org: http://healthiernation.org/about/accomplishments/ CIA - The World Factbook. (2013, April 2). Retrieved from Central Intelligence Agency: https://www.cia.gov/library/publications/the-world-factbook/ geos/am.html General Information About Breast Cancer. (2013, May 15). Retrieved from National Cancer Institute: http://www.cancer.gov/cancertopics/pdq/treatment/breast/Patient/pagel GLOBOCAN2008. (2013, April 2). Retrieved from International Agency for Research on Cancer: http://globocan.iarc.fr/ National statistical service: average nominal monthly salary in Armenia reaches 119, 791 in November 2012. (2013, April 4). Retrieved from arka.am: http://arka.am/en/news/society/national_statistical_service_average_nomi nal_monthly_salary_in_armenia_reaches_119_791_in_november_2/ Stages o f Breast Cancer. (2013, May 15). Retrieved from National Cancer Institute: http://www.cancer.gov/cancertopics/pdq/treatment/breast/Patient/page2 The KAP survey model - Medecins du Monde. (2013, April 1). Retrieved from medecinsdumonde.org. Anderson, B. 0., Yip, C.-H., Smith, R. A., Shyan, R., Sener, S. F., Eniu, A.,... Harford, J. (208]. Guideline Implementation for Breast Healthcare in Low-Income and Middle-lncome Countries. Cancer, 2221-43. Bhatt, V., Wetz, R., Shrestha, R., Shrestha, B., Shah, N., Sayami, P.,... Weiserbs, K. (2011). Breast cancer knowledge, attitudes and practices among Nepalese women. European Journal o f Cancer Care, 20, 810-7. Buck-Koehntop, B., & Defossez, P.-A. (2013). On how mammalian transcripton factors recognize methylated DNA. Epigenetics, 8 ,131-7. Croce, C. M. (2008). Oncogenes and Cancer. The New England Journal o f Medicine, 358, 502-11. Deroo, B., & Korach, K. (2006). Estrogen receptors and human disease. The Journal of Clinical Investigation, 561-570. Gilani, S., Khurram, M., Mazhar, T., Mir, S., Ali, S., Tariq, S., & Malik, A. (2010, March). Knowledge, attitude and practice of a Pakistani female cohort towards breast cancer. / Pak Med Assoc, 3, 205-8. Hollstein, M., Sidransky, D., Vogelstein, B., & Harris, C. C. (1991). p53 Mutations in Human Cancers. Science, 253,49-53. Kaufmann, R., Muller, P., Hildenbrand, G., Hausmann, M., & Cremer, C. (2011). Analysis of Her2/neu membrane protein clusters in different types of breast cancer cells using localization microscopy. Journal o f Microscopy, 46-54. [2005). 9.3 DNA is Packaged in Chromosomes. In D. Krogh, Biology A Guide to the Natural World (pp. 175-9). Upper Saddle River, New Jersey: Prentice-Hall. Launiala, A. (2009). How much can a KAP survey tell us about people's knowledge, attitudes and practices? Some observations from medical anthropology research on malaria in pregnancy in Malawi. Anthropology Matters, 11[ 1). Mah, Z., & Bryant, H. (1992, June 15). Age as a factor in breast cancer knowledge, attitudes and screening behaviour. CMAJ, 2167-2174. Mohibi, S., Mirza, S., Band, H., & Band, V. (2011). Mouse models of estrogen receptor-positive breast cancer. Journal o f Carcinogenesis, 35. Nagy, P., Jenei, A., Kirsch, A., Szollosi, J., Damjanovich, S., & Jovin, T. (1999). Activation-dependent clustering of the erbB2 receptor tyrosine kinase detected by scanning near-field optical microscopy. Jounal o f Cellular Science, 1733-41. National Statistical Service [Armenia], M. o. (2012). Armenia Demographic and Health Survey 2010. (2008). DNA Metabolism. In D. L. Nelson, & M. M. Cox, Principles o f Biochemistry (Fifth ed., pp. 975-1020). New York, New York, United States of America: W.H. Freeman and Company. (2008). Genes and Chromosomes. In D. L. Nelson, & M. M. Cox, Principles of Biochemistry (Fifth ed., pp. 947-74). New York, New York, United States of America: W.H. Freeman and Company. Nelson, D. L., & Cox, M. M. (2008). Lehninger Principles of Biochemistry. W.H. Freeman and Company. (2008). Nucleic Acid Chemistry. In D. L. Nelson, & M. M. Cox, Principles of Biochemistry [Fifth ed., pp. 271-302). New York, New York, United States of America: W.H. Freeman and Company. (2008). Oncogenes, Tumor Suppressor Genes, and Programmed Cell Death. In D. L. Nelson, & M. M. Cox, Lehninger Principles o f Biochemistry (pp. 473-9). New York, NY: W.H. Freeman and Company. (2008). Regulation of the Cell Cycle by Protein Kinases. In D. L. Nelson, & M. M. Cox, Lehninger Principles o f Biochemistry (pp. 469-73). New York, NY: W.H. Freeman and Company. Opoku, S., Benwell, M., & Yarney, J. (2012, February 17). Knowledge, attitudes, beliefs, behaviour and breast cancer screening practices in Ghana, West Africa. The Pan African Medical Journal, 11, 28. Patani, N., Martin, L.-A., & Dowsett, M. (2013). Biomarkers for the clinical managment of breast cancer: International perspective. International Journal o f Cancer, 133,1-13. Roemer, S., Donham, D., Sherman, L., Pon, V., Edwards, D., & Churchill, M. (2006). 2c7a Summary. Retrieved from Protein Data Bank in Europe: http://www.ebi.ac.uk/pdbe-srv/view/entry/2c7a/summary.html Satyanarayana, A., & Kaldis, P. (2009). Mammalian cell-cycle regulation: several Cdks, numerous cyclins and. Oncogene, 28, 2925-39. Shaikha, S. A., & Salama, R. (2011, Jul). Knowledge and Attitude towards Breast Cancer and Breast Self Examination among Women Attending Primary 36 Health Care Centres in Doha, 2009. Middle East Journal o f Family Medicine, 9, 8- 21. (2010). Apoptosis Is a Tidy Form of Cell Death. In D. U. Silverthorn, Human Physiology an Integrated Approach (Fifth ed., p. 85). San Francisco, California, United States of America: Pearson Benjamin Cummings. (2010). Communication, Integration, and Homeostasis. In D. U. Silverthorn, Human Physiology An Integrated Approach (Fifth ed., pp. 178-209). San Francisco, California, United States of America: Pearson Benjamin Cummings. Singletary, S. E., Allred, C., Ashley, P., Bassett, L. W., Berry, D., Bland, K. I.,... Greene, F. L. (2002). Revision of the American Joint Committee on Cancer staging system for breast cancer.J Clin Oncol, 3628-36. Walerych, D., Napoli, M., Collavin, L., & Del Sal, G. (2012). The rebel angel: mutant p53 as the driving oncogene in breast cancer. Carcinogenesis, 33, 2007-17. Yoshia, K., & Miki, Y. (2004). Role of BRCA1 and BRCA2 as regulators of DNA repair, transcription, and cell cycle in response to DNA damage. Cancer Science, 95,