Abstract C24: Interplay between ECM stiffness, miR-203 and mammographic density

Abstract

Abstract High mammographic density (MD) is associated with a greater risk of breast cancer and is characterized by high extracellular matrix (ECM) collagen. Elevated collagen increases ECM stiffness and can promote the malignant transformation of oncogenically-primed mammary epithelial cells in culture and in vivo. Whether or not high MD reflects a breast stroma that is stiff and if ECM stiffness accounts for the elevated breast cancer risk in high MD tissue and how has yet to be resolved. To address this question we are conducting a comprehensive biophysical and molecular analysis of BIRADS status in prophylactic mastectomies in women with low (BIRADS 1) versus high MD (BIRADS 4). Data revealed that the intra-lobular ECM associated with the terminal end-buds contains anisotropic compliant and relaxed collagen fibrils. By contrast, the inter-lobular ECM contains stiff, oriented collagen fibrils. Preliminary data suggest that the ECM associated with the terminal end-buds in the upper outer quadrant may be stiffer in women with high MD as compared to low MD. These same tissues also expressed lower levels of the microRNA miR-203, which has been implicated in epithelial-to-mesenchymal transition (EMT) inhibition. Consistently, in vitro studies revealed that miR-203 was repressed in MECs cultured on a stiff ECM. We also found that a stiffened mammary ECM decreases miR-203 expression and promotes an EMT. Additionally, inhibiting ECM stiffening restored miR-203 levels and reduced an EMT. Moreover and importantly, we showed that triple negative breast tumors that often express EMT markers have reduced miR-203 levels. Studies are underway to elaborate these preliminary findings and to assess their clinical relevance. (This work is supported by the: NIH NSRA T32 CA 108462-11 to Ivory Dean, Susan G Komen PDF12230246 to Irene Acerbi, W81XWH-13-1-0216, USMRAA DOD-BCRP BC122990, NIH R01 CA138818-01A1 and NIH R01 CA192914-01 to Valerie Weaver.) Citation Format: Ivory Dean, Irene Acerbi, Janna Mouw, Quanming Shi, Yunn-Yi Chen, Jan Liphardt, Shelley Hwang, Valerie Weaver. Interplay between ECM stiffness, miR-203 and mammographic density. [abstract]. In: Proceedings of the Ninth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2016 Sep 25-28; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(2 Suppl):Abstract nr C24.