Molecular Epidemiology, Racial/Ethnic Differences and Chemoprevention of Breast Cancer: Population-based Studies from Metropolitan Detroit.

Abstract

Breast cancer affects more women than any other cancer and is the second leading cause of cancer deaths among this group. Despite progress in our understanding of brest cancer risks and treatment improvements, there remain considerable knowledge gaps. The studies contained herein address some of these gaps; specifically, this dissertation focuses on health disparities, markers of progression, and prevention of breast cancer. Arab-Americans are an understudied minority, particularly because US population-based statistics do not separate them from “Caucasian”, resulting in lacking health statistics. In this dissertation, breast cancer characteristics at diagnosis are compared to European- and African-American women from the Detroit SEER tumor registry. Overall, Arab-American women have a distribution of breast cancer histology and overall survival similar to European-American women. Conversely, the stage, age, and hormone receptors at diagnosis among Arab-Americans were similar to African-American women. Molecular profiling of aggressive vs. non-aggressive early breast tumors is a strategy employed to investigate potential independent prognostic markers, RhoC and EZH2. RhoC, a Rho family GTPase, has been identified as a major phenotypic driver of inflammatory breast cancer, the most lethal form of breast cancer. EZH2 is a histonemethyltransferase polycomb group protein, which has been implicated in the process of cellular differentiation and cancer progression. Our results suggest that EZH2 is associated with hormonal receptor negativity, Her2 receptor positivity, cellular proliferation, family history, and being African-American. EZH2 positive tumors were significantly more likely to recur. However, the potential for RhoC to be a significant predictor of subsequent recurrence and/or distant metastasis for T1 breast cancers remains unresolved based on our study. Finally, we consider bisphosphonates, a class of drugs used primarily for osteoporosis, as breast cancer chemopreventive agents. Results reported here strongly support that bisphosphonates may be a potential chemopreventive agent. Indeed, our data suggest that exposure to bisphosphonates is associated with lowering breast cancer risk by half or more. This is comparable to the results of the trials involving tamoxifen, an approved breast cancer chemopreventive agent. In conclusion, this dissertation presents new knowledge about breast cancer characteristics in special populations, phenotypic markers, and support of a novel chemopreventive.