Abstract B91: BRCA1 mutation in breast cancer cells and generation of metastasis associated fibroblasts

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Abstract Tumor microenvironment plays an indispensable role in cancer development as it can be described as the territory where the interaction takes place between tumor and microenvironment elements such as the endothelial cells, epithelial cells, fibroblasts, immune cells, and ECM proteins. Among these structural stromal components, specifically cancer-associated fibroblasts (CAFs) have attracted substantial attention over recent decades. CAFs in the tumor microenvironment assist the accelerated growth demands of the cancer cells and enhance cancer progression through their paracrine activity by the enhanced secretion of growth factors and cytokines, which also help in remodeling the extracellular matrix (ECM). Studies reveal that CAFs have extended their role in cancer metastasis by accompanying the cancer cells to distant metastatic sites. From our in vitro studies, we have identified that coculturing the CAFs with the conditioned medium (CM) from BRCA1 mutated but not wild-type cancer cells results in the transformation of CAFs to an altered phenotype. Since these transformed CAFs showed increased migrative, invasive, and proliferative abilities, we named them “Metastasis Associated Fibroblasts” (MAF) (Sreelatha et al., 2018). The MAF thus generated showed a significant increase in the expression of the Ezrin, Radixin, and Moesin (ERM) protein complex, which may be attributed to the association of BRCA1 C-terminal (BRCT) domains of BRCA1 with the ERM protein superfamily. This association of BRCA1 with the key regulators of ERM complex can influence cell adhesion and motility, suggesting that BRCA1 may act upon their signaling pathways. To study the effect of BRCA1 mutation and ERM protein expression in CAFs in vivo, BRCA1 mutated breast cancer cells were orthotopically implanted to NOD-SCID mice. CAFs isolated from the tumor were analyzed for the expression of ERM. It was found that there is a significant increase in the expression of ERM protein in the tumors isolated from mice that were implanted with BRCA1 mutated breast cancer cells compared to the mouse group that received BRCA1 wild-type breast cancer cells. Inhibitors to ezrin and CCL5 could effectively reduce the metastatic potential of BRCA1 mutant cancer models. A combination of ezrin inhibitor (NSC 668394) and plumbagin, a plant-derived naphthoquinone that effectively reduces BRCA1 mutant breast cancer cell proliferation, is under investigation. Citation Format: Neetha Rajan Latha, Geetu Rose Varghese, Vishnu Sunil Jaikumar, Arathi Rajan, Revathy Nadhan, Arathy Warrier, Priya Srinivas. BRCA1 mutation in breast cancer cells and generation of metastasis associated fibroblasts [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr B91.