Abstract B053: Expression of alternative mRNA splicing variant MBD2_v2 promotes triple-negative breast cancer tumor initiation and is associated with body mass index

Abstract

Abstract According to epidemiologic research, obesity is a risk factor for triple-negative breast cancer (TNBC). The underlying molecular biology remains unknown. We reasoned that obesity-induced chronic inflammation, reactive oxygen species (ROS) being central, serves as the general link to TNBC. We are the first to report that expression of the epigenetic reader methyl-CpG-binding domain protein 2 mRNA variant MBD2_v2 in TNBC cell cultures depends on ROS and is necessary to maintain and promote 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 they give rise to drug resistance and metastatic recurrence. We also previously reported evidence that MBD2_v2 expression underlies TNBC resistance to EGFR inhibitor drugs. Now, having used a diet-induced obesity (DIO) mouse model that mimics human obesity, we report that MBD2_v2 and serine/arginine-rich mRNA splicing factor 2 (SRSF2) levels were increased in tumors that formed more frequently in DIO mice relative to lean controls. To more directly test if increased MBD2_v2 drives increased tumor initiation capacity, we stably modified MBD2_v2 or SRSF2 expression in TNBC cells prior to inoculation. MBD2_v2 overexpression increased tumor initiation while SRSF2 knockdown, resulting in decreased MBD2_v2 expression, attenuated tumor formation. In addition, our analysis of TNBC patient tumors revealed a significant positive association for MBD2_v2 expression and body mass index (BMI). African American (AA) women are 1.7 times more often obese relative to European American women, and a TNBC driver mechanism fueled by obesity-coupled inflammation could underlie the higher incidence of TNBC among AA women. Citation Format: Emily A. Teslow, Cristina Mitrea, Bin Bao, Ramzi M. Mohammad, Lisa A. Polin, Greg Dyson, Kristen S. Purrington, Aliccia Bollig-Fischer. Expression of alternative mRNA splicing variant MBD2_v2 promotes triple-negative breast cancer tumor initiation and is associated with body mass index [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr B053.