FP16-3 Stiff Collagen Matrices Increase Tumorigenic Prolactin Signaling in Breast Cancer Cells

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: FP16-Cancers of Endocrine Organs: Mechanisms of Tumorigenesis & Progression
Sunday, June 16, 2013: 10:45 AM-11:15 AM
Presentation Start Time: 10:55 AM
Room 206 (Moscone Center)

Poster Board SUN-293
Craig Barcus*1, Patricia Keely2, Kevin Eliceiri2 and Linda A Schuler3
1University of Wisconsin-Madison, Madison, WI, 2University of Wisconsin-Madison, 3Univ of WI, Madison, WI
Clinically, circulating prolactin levels and density of the extracellular matrix (ECM) are individual risk factors for breast cancer.  As tumors develop, the surrounding stroma responds with increased deposition and cross linking of the collagen matrix (desmoplasia).  In mouse models, prolactin promotes mammary carcinomas that resemble luminal breast cancers in women, and increased collagen density promotes tumor metastasis and progression.  Although the contributions of the ECM to the physiologic actions of prolactin are increasingly understood, little is known about the functional relationship between the ECM and prolactin signaling in breast cancer.  Here, we examined consequences of increased ECM stiffness on prolactin signals to luminal breast cancer cells in 3D collagen I matrices in vitro.  We showed that matrix stiffness potently regulates a switch in prolactin signals from physiologic to pro-tumorigenic outcomes.  Compliant matrices promoted physiological prolactin actions and activation of STAT5, while stiff matrices promoted pro-tumorigenic outcomes, including increased matrix metalloproteinase-dependent invasion and collagen scaffold realignment.  In stiff matrices, prolactin increased SRC-family kinase-dependent phosphorylation of focal adhesion kinase (FAK) at tyrosine 925, FAK association with the MAP kinase mediator, GRB2, and pERK1/2.  Stiff matrices also increased co-localization of prolactin receptors and integrin-activated FAK, implicating altered spatial relationships.  Together, these results demonstrate that ECM stiffness is a powerful regulator of the spectrum of prolactin signals, and that stiff matrices and prolactin interact in a feed-forward loop in breast cancer progression.  Our study is the first reported evidence of altered ECM-prolactin interactions in breast cancer, suggesting the potential for new therapeutic approaches.

Nothing to Disclose: CB, PK, KE, LAS

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: This work was supported by R01CA157675 (L.A.S.), R01CA142833 and R01CA114462 (P.J.K.), R01CA136590 (L.O.C.I.), Regenerative Biology Scholar’s Award, Biological Sciences Scholar’s Award, and Cellular and Molecular Biology Travel Grant (C.E.B.) and Comparative Biosciences, UW School of Veterinary Medicine.