Abstract B62: Perturbed myoepithelial cell differentiation in BRCA mutation carriers and in DCIS (ductal carcinoma in situ)

Abstract

Abstract The normal mammary gland is composed of multiple cell types, including luminal and myoepithelial cells. Myoepithelial cells have also been referred to as natural tumor suppressors due to their inhibitory effect on various neoplastic phenotypes, including tumor cell growth, invasion, and angiogenesis. We have previously determined that DCIS-associated myoepithelial cells lack clonal genetic aberrations, but their DNA methylation and gene expression patterns are distinct from that of normal myoepithelial cells, implying perturbed differentiation. We also showed that myoepithelial cells play key roles in preventing tumor growth and invasive progression in experimental models of DCIS, and in immune escape in breast cancer. These data support the hypothesis that the progressive loss of normal myoepithelial cell function in DCIS is a key step in the transition to invasive breast carcinomas, and assessing myoepithelial markers may identify patients with high risk of progression. However, the mechanisms underlying myoepithelial cell aberrations and eventual loss in DCIS are not well understood. In the present study, we used a combination of genomic profiling of human tissue samples and functional assays in a DCIS model to investigate regulators of normal myoepithelial cells and perturbations of these in BRCA mutation carriers and in DCIS. We first explored cellular heterogeneity of the CD10+ cell population in normal human breast tissues of nulliparous and parous women, from reduction mammoplasties and BRCA1 and BRCA2 mutation carriers undergoing prophylactic mastectomy. We identified two distinct CD10+ cell populations distinguished by the expression of CD44 and characterized their gene expression profiles. We also profiled CD10+ cells from BRCA1 and BRCA2 mutation carriers compared to normal noncarriers and found a clear separation of three distinct groups reflecting germline mutation status. Next we defined the p63 cistrome and the enhancer landscape of normal myoepithelial cells and identified alterations of these due to germline BRCA mutation status. Based on our initial results, we focused in p63 and TCF7 as these two transcription factors appear to be central for establishing myoepithelial cell fate. To address the functional relevance of p63 and TCF7 in myoepithelial cell differentiation, we used the MCFDCIS xenograft model of DCIS. These results support the hypothesis that myoepithelial cells play key roles in invasive progression and have significant impact on our understanding of DCIS progression and the increased breast cancer risk of BRCA mutation carriers. Citation Format: Lina Ding, Ying Su, Muhammad Ekram, Sung Jin Huh, Noga Bloushtain-Qimron, Sibgat Choudhury, William Hines, Jun Yao, Mina Bissell, Kornelia Polyak. Perturbed myoepithelial cell differentiation in BRCA mutation carriers and in DCIS (ductal carcinoma in situ) [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr B62.