| Description |
Breast cancer is a common disease affecting 1 in 8 women during their lifetime in the United States. Current strategies to manage breast cancer include chemotherapy, surgery, radiation, and targeted therapies. Despite intrapatient heterogeneity, breast cancers share common hallmark phenotypes of cancer as well as possess phenotypes that vary across tumors. Aside from traditional subtype determination using immunohistochemistry, breast tumors are typically profiled at the DNA level alone to determine patient eligibility for targeted therapies. Thus, the implementation of gene expression profiling could revolutionize breast cancer treatment by matching patients to targeted therapies based on the biological phenotypes of their tumors. This dissertation examines the biology of aggressive phenotypes in breast cancer, including the multidrug resistance, metaplastic, and elevated MAPK activity phenotypes. Resistance to systemic therapeutic interventions can be driven by overexpression of ATP-binding cassette transporter family member genes, including ABCB1 and can lead to poor outcomes in patients. Therapeutic strategies to inhibit the MDR1 protein encoded by ABCB1 have been unsuccessful in the clinic; therefore, implementation of other strategies to reverse the multidrug resistance phenotype driven by ABCB1 overexpression are warranted. Identification of equal sensitivity of ABCB1-overexpressing and GFP-overexpressing breast cancer cell lines to metabolic inhibitors suggests these inhibitors could be prescribed to patients with multidrug resistant cancers for improvement of outcomes. Metaplastic breast cancer (MpBC) is a rare and aggressive histological subtype of breast cancer with few therapeutic options. Despite aggressive treatment, patients with MpBC experience poor outcomes. Identification of AKT1, BCL2L11, and SNAI1 pathway activity in metaplastic breast tumors possessing mesenchymal histology suggests these patients may respond to targeted therapies aimed at these pathways. Further, patients with increased activity of an invasiveness gene expression signature experienced worse outcomes, indicating prevention of invasiveness phenotype may also lead to improved outcomes for MpBC patients. Finally, identification of patients with high MAP kinase pathway activity despite lack of driver mutations in MAP kinase pathway genes suggests patients may benefit from targeted therapies blocking MAPK signaling even if they lack these mutations. Additional research is required to test therapies capable of reversing these three aggressive breast cancer phenotypes in patient populations. |
