Elucidation Of Mechanisms In Mammary Tumorigenesis And Identification Of Driving Events And Susceptibility Loci
Human breast cancer research faces limitations necessitating a comparative oncogenomic approach and use of models, in which the environment and genetic background can be controlled. The Mcm4Chaos3 (Chaos3) mouse model contains the only endogenous mutation in mice known to lead exclusively to spontaneous development of mammary adenocarcinomas. My comparative analysis of Chaos3 and human oncogenomic data implicate NF1 deficiency as a major driver of breast cancer. Traditionally known for its tumor suppressive role in preventing neurofibromas, I find NF1 is deficient in Chaos3 mammary tumors and 27.7% of human breast tumors, including >40% of Her2-enriched and basal-like subtypes. NF1 loss triggered hyperactivation of the RAS oncogene, and these tumor cells were sensitive to RAS pathway drugs. As NF1 deficiency confers increased resistance to standard tamoxifen treatment, my findings have considerable implications for NF1 testing and personalized treatment that we project impacts ~383,230 women who develop breast cancer with NF1 deficiency annually. ~25% of breast cancer cases have a heritable/familial basis, but underlying susceptibility genes remain largely unknown. While, Chaos3-C3H mice develop mammary tumors, Chaos3-C57BL/6 mice develop lymphomas and histiocytic sarcomas, indicating that cancer type is highly influenced by background strain. We utilized Chaos3 mice of mixed backgrounds to identify mammary tumor susceptibility and resistance loci. Quantitative trait loci (QTL) analysis of ~200 C3H x C57BL/6 F2 Chaos3 females revealed candidate genes involved in cell proliferation, DNA repair, cell signaling, and cancer-associated genes. One locus contained Tln1, a gene required for integrin activation, in which a germline mutation was discovered. Chaos3 Tln1 mutants were aged, and a significantly higher proportion developed mammary tumors, validating Tln1 impact on mammary tumor susceptibility. In another set of studies, I found that DNA damage response (DDR) deficiency and reproductive hormones have a significant impact on carcinogenesis when MCM DNA replication machinery is defective. ATM pathway deficiency in Chaos3 mice resulted in decreased tumor latency and/or increased tumor susceptibility. Oophorectomized Chaos3 mice had decreased mammary tumor incidence, but increased susceptibility to other cancer types. Together, my results in four areas of breast cancer research demonstrate significant advancement in the understanding of mechanisms involved in mammary tumorigenesis.
Breast Cancer; Cancer Drivers and Susceptibility Loci; Chaos3; mcm; nf1; tln1
Schimenti, John C.
Clark, Andrew; Weiss, Robert S.
Ph. D., Genetics
Doctor of Philosophy
dissertation or thesis