Identification of novel prognostic markers in triple-negative breast cancers in African American Women

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Project Summary Triple negative breast cancer (TNBC) is characterized by lack of expression of the estrogen receptor (ER), progesterone receptor (PR), and the human epidermal growth factor receptor 2 (HER2). Available chemotherapy for TNBC results in limited efficacy and significant toxicity. The majority of patients with metastatic disease do not survive beyond 3 years. Currently, no targeted therapies are available for TNBC, in part because it is a highly heterogeneous disease and because the molecular drivers for TNBC are not known. TNBC more frequently affects younger patients (< 50 years) and is twice as prevalent in African American women as compared to Caucasians. There is a need to understand the biology of TNBC at the basic genetic and epigenetic levels to be able to develop targeted therapies for individual patients. We have identified a cohort of long non-coding RNAs (lncRNAs) that may be specific to TNBC in African American women. The proposed research is focused on understanding the function of these lncRNAs in TNBCs. We hypothesize that disparities in TNBC in the African American population may be explained, in part, by expression of non-coding RNAs and epigenetic alterations that are specific to this population. We propose that lncRNAs may play an important role in the initiation and progression of TNBC in this population through regulation of gene expression. This proposal, consisting of two Specific Aims, will powerfully harness the complementary expertise of a team of investigators with considerable experience in signal transduction, cell cycle control, gene regulation, and clinical aspects of breast cancer. In Aim 1, we will test the hypothesis that down-regulation of selected "driver lncRNAs" will significantly affect TNBC cell proliferation, cell cycle progression, survival, migration, and invasion in TNBC using in vitro models of this disease. In Aim 2, we propose to characterize the most promising lncRNAs using an animal model, in an effort to understand how they initiate and maintain the TNBC phenotype and the associated gene expression signature.