Breast cancer is the most diagnosed cancer in women in the United States and throughout the world. Current estimates have approximately 1 out of every 8 women will get breast cancer at some point in their lifetime, while 1 out of every 39 women will ultimately die from breast cancer in the United States. Breast cancer is a heterogeneous disease, with no two patients’ breast cancers being exactly alike. The research and medical communities have spent a significant amount of effort to characterize and classify breast cancers into meaningful subtypes that represent different possible treatment modalities. Despite treatment advances in targeting specific breast cancer subtypes, we still lack effective treatment options for various subtypes of breast cancer and patients with advanced/metastatic breast cancer. A large domain of cancer research centers around attempting to mimic human breast cancer subtypes in mice to mechanistically study oncogenes and tumor suppressors in controlled environments. Identification of mouse models representative of human breast cancer subtypes would enable sensitive and specific therapeutic development targeting breast cancer subtypes while limiting systemic toxicity. One of the ways researchers classify breast cancers into meaningful categories is through intrinsic subtypes, where breast cancer subtypes are defined by differential expression of key genes known to be involved in oncogenic signaling pathways unique to each subtype. The differential expression of these genes often stems from acquired genomic alterations. I hypothesize that comparative genomics betweenhuman breast cancer subtypes and mouse models of breast cancer would allow identification of additional genomic oncogenic driver events, potentially establishing links between specific mouse models of breast cancer to human breast cancer subtypes. Follow up in vitro and in vivo mechanistic studies can then be used to validate computational findings to confirm putative oncogenic drivers. To this end, I analyzed the genomes of spontaneous primary mammary gland tumors from different mouse models of breast cancer, focusing on the MMTV-Cre E2F5 conditional knockout, MMTV-Myc, and MMTV-Neu mouse models. In summary, I found that MMTV-Cre driven E2F5 conditional knockout in the murine mammary gland resulted in highly heterogeneous genomic alterations, but most tumors independently developed amplification events centered on Wnt2, Met, Cav1, and Cav2, while also possessing the same highly impactful splice acceptor mutation in Fbxo15. The MMTV-Myc mouse model of breast cancer generates several distinct histological subtypes, from which I identified that the EMT histological subtype coalesces on heterogeneous activation of the Kras pathway through Kras activating mutations or Fgfr2 amplification, while the microacinar subtype develops co-occurring mutations in Kit and Rara and amplifications over chromosomes 11 and 15. Finally, I interrogated the previously discovered 17q21.33 amplicon centered over putative oncogenes COL1A1, CHAD, and PHB1 involved in metastasis in HER2+ breast cancer. I found increased breast cancer metastasis signatures and increased estrogen signaling but failed to identify the specific role each gene played in the metastatic cascade. These results underscore the potential impact of genomic sequencing in mouse models of breast cancer and their applicability to studying human breast cancer development and treatment.
Read
