Racial Disparities in Breast Cancer and the role of micro-RNAs

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DESCRIPTION (provided by applicant): There is a racial disparity in the breast cancer outcomes between African-American (AA) and Caucasian (CA) women. For example, mortality rates for breast cancer in AA women can be three times higher than for CA, even though the incidence is lower in AA women (1). AA women develop triple-negative breast cancer (TNBC) at earlier age, more often diagnosed with advanced stage, likely to experience metastasis and often unresponsive to treatment compared to CA women (1, 2). Although some patients respond to chemotherapy, initially, tumor recurrence within 1 to 3 years post chemotherapy with high incidence of mortality occurring by 5 years (3). Our research group and others have reported that cancer stem-like cells (CSCs or tumor initiating cells), which are characterized by their self-renewal and resistance to therapy leading to tumor recurrence and metastasis, are particularly abundant in women with TNBC compared to those with other types of breast cancer (4, 5). We have also observed that isolated CSCs in CRL-2335 and MDA-MB468 cell lines derived from AA TNBC patients (i) showed significantly longer survival and the ability to form mammospheres compared to those CSCs in MDA-MB-231 and BT549 cell lines derived from CA TNBC patients (ii) after treatment with cisplatin plus tumor-necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), exhibited decreased expression of miR-100 and miR-23b and significant increase in FZD8, one of the Wnt receptors (also a target for miR-100) which plays a major role in CSC renewal, as compared to those seen in MDA-MB-231 and BT549 cell lines derived from CA TNBC patients. Hence, we hypothesized that differences in the self- renewal of cancer stem cells (CSCs) contributes to the racial disparities in TNBC. In order to test our hypothesis, we have two specific aims: Aim 1: Determine the role of CSCs in TNBC in African-American women compared to Caucasian women. Aim 2: Develop a new tumor model to address the role of microRNAs (miR-100 and miR-23b) in CSCs self- renewal, tumor progression and treatment in vivo. Successful completion of the proposed studies will give insights into the molecular biology of CSCs and their role, if any, in racial differences between AA and CA TNBC patients and, also provide new targets for their elimination for effective therapy.