Genetic and phenotypic evolution of breast cancer through years of treatment

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Title Genetic and phenotypic evolution of breast cancer through years of treatment
Publication Type thesis
School or College School of Medicine
Department Biomedical Informatics
Author Brady, Samuel
Date 2017-08
Description Acquired drug resistance is a frequent challenge in breast cancer. A tumor may initially respond to chemotherapy, but later become resistant and relapse. This is largely due to intra-tumoral heterogeneity; tumor genetic subclones with higher fitness in response to chemotherapy survive, and the patient’s cancer becomes drug-resistant. In additional, non-genetic phenotypic alterations in response to chemotherapy may promote drug resistance. How breast cancers evolve to become drug-resistant is unclear. A better understanding of how this occurs could lead to alternative therapeutic regimens to treat drug-resistant breast cancer or prevent its development. To address this problem, we performed genomic and phenotypic analysis of four breast cancers through 2 to 15 years of diverse treatments, using a unique set of longitudinal samples from these patients. This revealed genetic events likely leading to drug resistance, including acquisition of BRCA2 reversions and ABCB1 fusions. Further, cancer phenotypes evolved dramatically after treatment, including increased post-treatment mesenchymal, receptor tyrosine kinase, and immune avoidance gene expression profiles. In one patient, treatment of cultured patient cells with drugs targeting the receptor tyrosine kinase phenotype was more effective in post-treatment, receptor tyrosine kinase-high cells compared to the pre-treatment cells. Thus, we have identified both mutations and phenotypes that may promote breast cancer drug resistance, some of which may be targeted to treat drug-resistant cancers.
Type Text
Publisher University of Utah
Subject MESH Breast Neoplasms; Receptor Protein-Tyrosine Kinases; Phenotype; Drug Resistance, Neoplasm; Antineoplastic Combined Chemotherapy Protocols; Dose-Response Relationship, Drug; Gene Expression Profiling; Mammary Glands, Human; Neoplastic Stem Cells; Molecular Targeted Therapy
Dissertation Institution University of Utah
Dissertation Name Master of Science
Language eng
Relation is Version of Digital version Genetic and Phenotypic Evolution of Breast Cancer Through Years of Treatment
Rights Management Copyright © Samuel Brady2017
Format application/pdf
Format Medium application/pdf
Source Original in Marriott Library Special Collections
ARK ark:/87278/s66h8nr9
Setname ir_etd
ID 1347650
Reference URL https://collections.lib.utah.edu/ark:/87278/s66h8nr9
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