Stiff Collagen Matrices Increase Tumorigenic Prolactin Signaling in Breast Cancer Cells

• Published in: The Journal of biological chemistry Vol. 288; no. 18; pp. 12722 - 12732
• Main Authors: Barcus, Craig E., Keely, Patricia J., Eliceiri, Kevin W., Schuler, Linda A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 03-05-2013; American Society for Biochemistry and Molecular Biology
• Subjects: Animals; Breast Cancer; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cell Biology; Cell Line, Tumor; Collagen; Collagen Type I - genetics; Collagen Type I - metabolism; Density; Desmoplasia; Extracellular Matrix; Extracellular Matrix - genetics; Extracellular Matrix - metabolism; Extracellular Matrix - pathology; Female; Focal Adhesion Kinase; Focal Adhesion Kinase 1 - genetics; Focal Adhesion Kinase 1 - metabolism; GRB2 Adaptor Protein - genetics; GRB2 Adaptor Protein - metabolism; Humans; Mammary Neoplasms, Animal - genetics; Mammary Neoplasms, Animal - metabolism; Mammary Neoplasms, Animal - pathology; MAP Kinase Signaling System; Mice; Mitogen-Activated Protein Kinase 1 - genetics; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - genetics; Mitogen-Activated Protein Kinase 3 - metabolism; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Phosphorylation - genetics; Prolactin; Prolactin - genetics; Prolactin - metabolism; STAT5 Transcription Factor - genetics; STAT5 Transcription Factor - metabolism; Desmoplasia; Extracellular Matrix; Prolactin; Collagen; Focal Adhesion Kinase; Breast Cancer; Density
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M112.447631

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 three-dimensional collagen I matrices in vitro. We showed that matrix stiffness potently regulates a switch in prolactin signals from physiologic to protumorigenic outcomes. Compliant matrices promoted physiological prolactin actions and activation of STAT5, whereas stiff matrices promoted protumorigenic 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 mitogen-activated protein 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.
Background: Prolactin, but not its best studied mediator STAT5a, is associated with breast cancer progression.
Results: In stiff but not compliant collagen matrices, prolactin promotes tumorigenic processes via an enhanced ERK1/2 cascade.
Conclusion: Extracellular matrix stiffness powerfully modulates the spectrum of prolactin signals and actions.
Significance: Prolactin and stiff matrices interact in a feed-forward loop in breast cancer, suggesting new therapeutic approaches.