Abstract PR01: Understanding the role of BCL11A in triple-negative breast cancer

Abstract

Abstract Triple-negative breast cancer (TNBC) has poor prognostic outcome compared to other subtypes of breast cancer. The molecular and cellular mechanisms underlying TNBC pathology are not fully understood. We analyzed both METABRIC and TCGA data found the transcription factor BCL11A is overexpressed in TNBC including basal-like breast cancer (BLBC) and that its genomic locus is amplified in up to 38% of BLBC tumors. Moreover, analysis of the TCGA data revealed that the BCL11A locus is hypo-methylated almost exclusively in BLBC tumors but not other subtypes. We show that exogenous BCL11A overexpression promotes tumor formation, whereas its knockdown in TNBC cell lines suppresses their tumorigenic potential in xenograft models. In the mouse DMBA-induced tumor model, Bcl11a deletion substantially decreases tumor formation, even in p53-null cells and inactivation of Bcl11a in established tumors causes their regression. At the cellular level, Bcl11a deletion causes a reduction in the number of mammary epithelial stem and progenitor cells. Mechanistically, proteomics studies have revealed that BCL11A interacts with a specific set of chromatin modifiers in tumor cells but not in normal cells - the significance of which is currently under investigation. This study highlights the potential for targeting BCL11A as an approach for TNBC-targeted therapy. To this end we are currently using the Crispr/Cas9 system to generate endogenous reporter cell lines for high-throughput drug screens to identify potential inhibitors of BCL11A. Citation Format: Kyren Lazarus, Carlos Caldas, Pentao Liu, Walid T. Khaled. Understanding the role of BCL11A in triple-negative breast cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research; Oct 17-20, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(2_Suppl):Abstract nr PR01.