Abstract PR04: Tissue tension promotes mammary stemness and breast cancer aggression

Abstract

Abstract Breast cancers frequently develop treatment resistance that leads to recurrence, dissemination and patient mortality. Among the mechanisms that foster treatment resistance is the ability of tumor cells to undergo an epithelial-to-mesenchymal transition (EMT) and exhibit stem-like behavior. Accumulating evidence now supports the concept that the mechanical properties of the extracellular matrix microenvironment can critically influence developmental cell fate and modify several features of tumor progression. Data from our laboratory using preclinical models and clinical samples suggest that tissue tension and elevated mechanosignaling increase prior to and accompany malignant transformation. Therefore, we hypothesize that enhanced tissue mechanical tension and high mechanosignaling foster mammary stemness, EMT and breast cancer aggression. We tested this prediction by generating transgenic mice conditionally expressing a β1-Integrin clustering mutant (V737N) in the mammary epithelium. V737N expression stimulated integrin-mediated mechanosignaling in mammary epithelial cells (MECs), as determined by elevated phosphorylation of FAK and p130Cas, and this heightened mechanosignaling promoted precocious epithelial ductal branching, end bud formation and increased MEC proliferation in the mammary gland. These mammary phenotypes were accompanied by an increase in the ratio of basal/myoepithelial to luminal MECs in V737N mammary glands. Isolated V737N-expressing MECs possessed higher levels of genes associated with EMT and stemness, and Matrigel colony formation and transplantation assays revealed a functional increase in progenitor/stem cell frequency in the V737N-expressing basal/myoepithelial MECs compared to their corresponding controls. To examine the effect of tissue tension on breast cancer progression, we combined the V737N-β1-Integrin together with a mouse model of HER2-positive breast cancer (MMTV-NEU). While V737N expression had no observable effect on primary tumor outgrowth, overall tumor incidence and lung metastasis were significantly augmented. Further histological examination of tumors and gene expression analysis uncovered a phenotypic shift, such that V737N tumors displayed expression patterns resembling an EMT-like basal tumor when compared to control tumors. Thus, tissue tension by way of enhanced mechanosignaling promotes mammary stemness, higher mammary tumor incidence and a more basal-like aggressive tumor character. Potential V737N mechanistic actions currently under investigation involve altered orientation of cell divisions resulting from disrupted MEC polarity, as well as a heightened sensitivity to hormone-induced expansion of stem/progenitor cells. (Supp by: USMRAA Department of Defense-BCRP BC122990 and NIH NCI R01CA192914 to VW and AACR 15-40-01-NORT to JN). Citation Format: Jason J. Northey, Yoshihiro Yui, Janna K. Mouw, Johnathan N. Lakins, Valerie M. Weaver. Tissue tension promotes mammary stemness and breast cancer aggression. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research; Oct 17-20, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(2_Suppl):Abstract nr PR04.