Abstract 184: Three-dimensional density model promotes invasive characteristics in normal mammary epithelial cells

Abstract

Abstract Background: Breast cancer (BC) is the most diagnosed cancer and the fourth leading cause of cancer related mortality among women. One of the highest risk factors for developing BC is dense breast tissue. Mammographic density (MD) is defined by the amount of stromal and epithelial tissues present in the breast. Approximately, 50% of women in the US have high MD and are 4-6 times more likely to develop BC in their lifetime. The stromal microenvironment is characterized by extracellular matrix (ECM) reorganization and stiffness. One of the most abundant molecules in ECM is collagen type I (Col1). High Col1 expression is seen in women with high MD and is also correlated with cell proliferation, survival, and invasion. Unfortunately, the underlying cellular and molecular mechanisms for the association between MD and BC are poorly understood. Therefore, understanding the molecular pathways involved in the unique transformation of normal mammary epithelial cells (nMECs) to cancer cells in a dense microenvironment is an important step in finding diagnostic tools and therapeutic targets for prevention and treatment of BC. My hypothesis is that 3-dimensional (3D) collagen-dense matrix promotes an invasive phenotype and activates oncogenic cell signaling pathways in nMECs, and hTERT-HME1 cell line, contributing to their transformation. Methods: I conducted an in vitro study using hTERT cells cultured in 3D COL1-dense gels todetermine the phenotypical changes and cellular signaling alterations caused by high collagen density. Results: I have observed that hTERT cells in high 3D COL1-dense gels form invasive phenotypes with protrusive structure compared to cells in low density gels. My previous data shows that, hTERT cells cultured in 2D-COL1 coated plates will express mesenchymal markers and over-express ERK1/2 and PI3K pathways which promote cancer cell proliferation and tumor cell survival. My plan is to further analyze the oncogenic cell signaling pathways that drive the transformation of hTERT cells into invasive cells, using my 3D COL1-dense gels. These pro-oncogenic pathways include, MAPK pathway, PI3 Kinase pathway, the activation of Epithelial to Mesenchymal Transition (EMT) markers as well as the expression level of tumor-associated MUC1 (tMUC1) . Unlike MUC1, tMUC1 is hypo-glycosylated and is over expressed in more than 90% of invasive breast carcinomas. I plan to investigate the pathway of association between inflammation caused by dense tissue, MUC1 signaling and cell transformation that could drive carcinogenesis. Conclusion: A collagen-stiff mammary microenvironment can induce carcinogenic phenotypes and cell signaling behavior in nMECs, which highlights the possible first steps in the transformation of nMECs into cancer cells. Given that high MD is one of the major risk factors for BC development, it is critical to decipher the molecular mechanisms associated with the high risk. Citation Format: Shayan Nazari, Pinku Mukherjee. Three-dimensional density model promotes invasive characteristics in normal mammary epithelial cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 184.