mTOR pathway in breast cancer subtypes by race: A molecular pathological study

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Summary My career goal is to become an independent cancer epidemiologist using molecular approaches, including molecular pathology, to understand cancer etiology in the overall population and among different racial and ethnic sub-populations. While my doctoral research focused on nutritional factors in relation to lung, prostate, and colorectal cancers, upon arrival to Roswell Park Cancer Institute (RPCI), I became aware of the many complexities and unanswered questions in breast cancer research, particularly among African-American (AA) women, the population affected most by unfavorable breast cancer subtypes, i.e., estrogen receptor negative (ER–), triple-negative, and basal-like tumors. With a growing understanding of breast cancer subtypes and its importance in assessing risk factors and outcomes, I became motivated to learn more about pathology and studying characteristics at the tumor level. However, it soon became obvious that to succeed in this area, I needed more knowledge and experience in pathology and the molecular methods used in assessing subtypes and molecular markers in tumors. Therefore, through this K07 mechanism, I will develop the required expertise needed in molecular pathological epidemiology, including laboratory experience in pathology, and further train in breast cancer etiology. Among breast cancer risk factors, obesity and central adiposity are associated with breast cancer risk among AA women, and these associations may differ between tumor subtypes. However, the underlying mechanisms of the associations are largely unclear. Positive energy imbalance, a cause of obesity, can activate the phosphatidylinositol 3-kinase/AKT/mammalian target of the rapamycin (mTOR) pathway, which is important in regulation of cell growth and proliferation and has been implicated in breast cancer development. To better understand the role of the mTOR pathway in the association between obesity and breast cancer subtypes, I will conduct a molecular pathological epidemiology study leveraging tumor tissue and data from 1,400 AA and 433 European-American (EA) women with breast cancer in the Women’s Circle of Health Study (WCHS), currently supported by R01 CA185623. I aim to examine differences in mTOR pathway activities between ER+ and ER- breast tumors and between intrinsic subtypes, which include luminal A, luminal B, human epidermal growth factor receptor 2 (HER2)- overexpressing, and basal-like tumors, among AA women (Aim 1). The study will also assess the association of mTOR pathway activities with key components of obesity (general obesity, central adiposity, body composition, and weight gain) among AA women (Aim 2), and compare the associations of mTOR pathway activities with breast cancer subtypes, as well as with obesity, between AA and EA women (Exploratory Aim). The expectation of this research is to provide a better understanding of the extent to which obesity components are associated with mTOR pathway activities; whether the associations are more frequently observed for specific breast cancer subtypes in AA women; and whether these associations differ between AA and EA women. Also, we anticipate this research to shed light on preventive strategies for ER–, triple-negative, and basal-like breast cancer in AA women, which could assist in reducing the gap of breast cancer mortality between AA and EA women. The results of this project will serve as a stepping stone to developing a R01 project, which is likely to extend to examining molecular tissue markers in other obesity-related pathways in the African American Breast Cancer Epidemiology and Risk (AMBER) Consortium, a NCI Program Project grant (P01 CA151135). The proposed research project is well tailored for me to apply the knowledge and skills that will be obtained from training activities, and my primary mentor, Dr. Christine Ambrosone, who is a world- renowned expert in molecular epidemiology and breast cancer etiology and disparities, as well as PI of the WCHS and AMBER Consortium. I will also benefit from my co-mentors: Dr. Thaer Khoury (breast cancer pathology), Dr. Song Liu (statistical analyses in tumor marker data), and Dr. Elisa Bandera (breast cancer etiology in obesity and racial disparities). For further guidance, I enlist the expertise of molecular pathologist, Dr. Wiam Bashara, and from Dr. Deborah Erwin for consultation on result dissemination in minority groups. The training activities include pathology courses, a six-month rotation in molecular pathology laboratories, regular office-based rotations with Dr. Khoury, attendance and presentations at institute and international meetings, publication in molecular pathological epidemiology, R03 and R01 grant writing, continuing training in ethics/conduct of research, and participation in working groups and data collection activities. The research project and laboratory rotation will be supported by the P-30 CCSG Pathology Resources Network Shared Resource, which is also actively involved in the WCHS and AMBER Consortium. The long-existing partnership between the Pathology and Cancer Prevention and Control Departments at RPCI, and the multi-disciplinary setting for breast cancer research at RPCI, as well as the State University of New York University at Buffalo, provide an outstanding environment for me to achieve my research and career goals.