Determining the Roles of MYB Family Transcription Factors in Breast Tumorigenesis

A major advancement in the field of breast cancer research was the discovery of the breast tumor intrinsic subtypes made through the utilization of gene expression microarrays. Breast cancer can no longer be viewed as a single disease, but rather as at least five different diseases each with unique biological activity and clinical outcomes. Targeted therapy strategies are now employed to treat the different tumor types, such as estrogen receptor modulators for ER-positive disease, and HER2-inhibitors for the treatment of HER2-positive tumors. For tumors lacking therapeutic targets, patients are limited to cytotoxic chemotherapy regimens. Consequently, additional research is crucial in further elucidating the molecular pathways governing each breast tumor subtype. Over one thousand genes are used to stratify the intrinsic molecular subtypes; however, very few of these genes have been analyzed for their direct role in tumorigenesis. This dissertation focuses on investigating two intrinsic genes, B-Myb and c-Myb, which are both members of an evolutionarily conserved gene family first identified as transforming genes in avian viruses. B-Myb is highly expressed in basal-like tumors, whereas c-Myb is highly expressed in luminal tumors. We applied in vitro and in vivo analyses to ascertain the roles of these genes within the molecular subtypes. High B-Myb expression levels were predictive of poor outcomes across all breast tumors and within subtypes. Mammary epithelial cells expressing high levels of B-Myb were more sensitive to topoisomerase 2α inhibitors, but not other chemotherapeutics, via the induction of G2/M cell cycle genes including TOP2A itself. We identified the first published B-Myb germline variant causing an increased risk for basal-like disease. We found that the c-Myb oncogene was behaving as a tumor suppressor in luminal breast cancer through a novel p53 stabilization pathway. These results have significant treatment implications in light of an ongoing hematologic malignancies clinical trial in which c-Myb is targeted for knock-down through antisense oligonucleotides. These results point to both B-Myb and c-Myb as important breast cancer biomarkers with potential clinical importance for determining disease risk and guiding treatment, and provide important insight into the roles of MYB family proteins in the etiology of breast cancer