Human breast cancer is a diverse disease, exhibiting variety in morphology, natural history, and therapeutic response. Multiple studies have shown that breast tumors can be segregated into distinct subtypes, characterized by similarities in the genes they express. One subtype, called basal-like breast tumors (BBT), represents 10-20% of breast cancer diagnoses and is typically associated with poor outcomes. Our work has shown that BBT occurs with significantly higher frequency in women with germline mutations in breast cancer 1 (BRCA1). Given the link between BRCA1-germline mutations and BBT, we proposed to determine whether the BRCA1-dependent DNA repair pathway is deficient during sporadic BBT formation.
Our initial step was to identify BBT specific regions of aberration and determine if they affected important genetic pathways. One region located on chromosome 5q contained multiple BRCA1-dependent repair pathway genes. These genes exhibited frequent co-associated loss with each other and with other cancer relevant genes. Exogenous disruption of these genes in normal breast epithelial cell lines increased sensitivity to DNA damage and impaired BRCA1 localization and function.
We further characterized the genomic instability aspect of BBT by examining a previously undetectable form of genomic aberration we termed micro-aberrations. These small-scale genomic changes (<5kb in some cases) are detectable using a high-resolution tiling array. We found these events were functional, relevant for survival, preferentially located in the promoter regions of cell cycle genes, and appear most frequently in BBT.
Lastly, we examined BBT-specific loss of the tumor suppressor INPP4B. We found that DNA, RNA, and protein expression of INPP4B are highly correlated with BBT and that it functions as an excellent marker of this subtype as well as predicting survival and response to therapy.
It is critical to gain a greater understanding of BBT function as BBT poses a significant challenge to the US health care system; if BBT were to be treated as a unique disease separate from other breast cancers, it would represent the fourth leading cause of cancer deaths among women. My work here describes newly discovered functional basal-specific aberrations that explain much of the biology of BBT.
|Advisor:||Perou, Charles M.|
|Commitee:||Kaufmann, William K., Rathmell, Wendy Kimryn, Richards, Kristy L., Troester, Melissa A.|
|School:||The University of North Carolina at Chapel Hill|
|Department:||Genetics & Molecular Biology|
|School Location:||United States -- North Carolina|
|Source:||DAI-B 73/11(E), Dissertation Abstracts International|
|Subjects:||Molecular biology, Genetics, Medicine, Oncology|
|Keywords:||BRCA1, Breast cancer, Copy number, DNA repair, Gene expression, Genomics, Molecular subtypes|
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