Abstract 3680: SRSF2-dependent MBD2v2 expression is induced by obesity and promotes tumor-initiating triple negative breast cancer stem cells

Abstract

Abstract Obesity is a risk factor for triple negative breast cancer (TNBC) incidence and poor outcomes, the underlying molecular biology of which remains unknown. We previously identified in TNBC cell cultures that expression of epigenetic reader methyl-CpG-binding domain protein 2 (MBD2), specifically the alternative mRNA splicing variant MBD2v2, is dependent on reactive oxygen species (ROS) and is crucial for maintenance and expansion of cancer stem cell-like cells (CSCs). The relevance of CSCs is that they are a subpopulation of cancer cells recognized as the source of malignant tumor initiation, and give rise to drug resistance and metastatic recurrence. Because obesity is coupled with inflammation and ROS, we hypothesized that obesity could fuel an increase in MBD2v2 expression to promote the tumor-initiating CSC phenotype in TNBC cells in vivo. In this study we sought to characterize the role of obesity in regulating MBD2v2 expression in TNBC tumors, and better understand the mechanism regulating MBD2v2 expression in TNBC cells. Analysis of TNBC patient datasets revealed associations between high tumor MBD2v2 expression and high relapse rates and body mass index (BMI). Stable gene knockdown/overexpression methods were applied to TNBC cell lines to elucidate that MBD2v2 expression is governed by ROS-dependent expression of the serine and arginine-rich splicing factor 2 (SRSF2). Analysis of TNBC patient datasets also revealed an association between high tumor SRSF2 expression and high relapse rates and BMI. We employed a diet-induced obesity (DIO) mouse model to investigate if obesity influenced MBD2v2 expression and increased tumor initiation capacity of inoculated TNBC cell lines. MBD2v2 and SRSF2 levels were increased in TNBC cell line-derived tumors, which formed more frequently in DIO mice, relative to tumors in lean control mice. Stable MBD2v2 overexpression increased the CSC fraction in culture and increased TNBC cell line tumor initiation capacity in vivo. SRSF2 knockdown resulted in decreased MBD2v2 expression, decreased CSCs in TNBC cell cultures and hindered tumor formation DIO mice. The data provide concurring evidence that SRSF2-regulated MBD2v2 expression is induced by obesity and drives TNBC cell tumorigenicity, and thus provides molecular insights in support of the epidemiological evidence that obesity is a risk factor for TNBC. The majority of TNBC patients are obese and rising obesity rates threaten to further increase the burden of obesity-linked cancers, which reinforces the relevance of this study. Citation Format: Emily A. Teslow, Cristina Mitrea, Bin Bao, Ramzi M. Mohammad, Lisa A. Polin, Gregory Dyson, Kristen S. Purrington, Aliccia Bollig-Fischer. SRSF2-dependent MBD2v2 expression is induced by obesity and promotes tumor-initiating triple negative breast cancer stem cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3680.