Abstract A33: The role of microRNA-181a in TGF-β-mediated breast cancer progression

Abstract

Abstract Transforming growth factor-beta (TGF-β) is a multifunctional cytokine that functions to inhibit breast cancer development in the normal mammary epithelium by inducing cell cycle arrest, and maintaining microenvironmental homeostasis through extracellular matrix (ECM) deposition and remodeling. Mammary tumorigenesis causes a loss in TGF-β-mediated cytostasis and leads to a switch in TGF-β function, whereby TGF-β promotes epithelial-mesenchymal transition (EMT), proliferation, invasion and metastasis. This switch in TGF-β function, from tumor suppressor to tumor promoter, is referred to as the “TGF-β paradox” and occurs through molecular mechanisms that remain incompletely understood. Moreover, this switch in TGF-β function is often accompanied by desmoplastic and fibrotic reactions, leading to the formation of a more rigid microenvironment, which in and of itself has been associated with tumor progression. We have shown that tissue compliance and extracellular matrix rigidity mediate how cells sense and respond to TGF-β. Indeed, we can recapitulate the “TGF-β paradox” by exposing metastatic breast cancer cells to compliant ECM signals, which reinstates the cytostatic activities of TGF-β. As a possible mechanism for the influence of matrix rigidity on TGF-β signaling, we sought to define the miRNA expression profiles induced by TGF-β in metastatic cells as compared to their non-metastatic counterparts when grown in either compliant or rigid conditions. We show that ECM rigidity regulates the miRNA expression signature induced by TGF-β in breast cancer cells. From this miRNA signature, we have identified the miR-181 family as a miR family that is highly upregulated in metastatic cells in response to TGF-β. Additionally, over-expression of a miR-181a mimic enhances TGF-β-mediated invasion. Conversely, treating cells with a hairpin inhibitor directed against miR-181a inhibits TGF-β-mediated invasion, EMT, and survival signaling. Furthermore, inhibition of miR-181a abrogates pulmonary outgrowth and enhances overall survival in vivo. Collectively, our findings identify the miR-181a family as a novel effector of TGF-β-driven tumor progression and suggest that measures capable of diminishing miR-181a levels may alleviate breast cancer progression. [FY09-DOD-BCRP-Predoctoral Traineeship Award]. Citation Format: Molly A. Taylor, William P. Schiemann. The role of microRNA-181a in TGF-β-mediated breast cancer progression [abstract]. In: Proceedings of the AACR Special Conference on Noncoding RNAs and Cancer; 2012 Jan 8-11; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(2 Suppl):Abstract nr A33.