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Caveolin-1−/− Null Mammary Stromal Fibroblasts Share Characteristics with Human Breast Cancer-Associated Fibroblasts

By Federica Sotgia, Francesco Del Galdo, Mathew C. Casimiro, Gloria Bonuccelli, Isabelle Mercier, Diana Whitaker-Menezes, Kristin M. Daumer, Jie Zhou, Chenguang Wang, Sanjay Katiyar, Huan Xu, Emily Bosco, Andrew A. Quong, Bruce Aronow, Agnieszka K. Witkiewicz, Carlo Minetti, Philippe G. Frank, Sergio A. Jimenez, Erik S. Knudsen, Richard G. Pestell and Michael P. Lisanti

Abstract

Recently, we reported that human breast cancer-associated fibroblasts show functional inactivation of the retinoblastoma (RB) tumor suppressor and down-regulation of caveolin-1 (Cav-1) protein expression. However, it remains unknown whether loss of Cav-1 is sufficient to confer functional RB inactivation in mammary fibroblasts. To establish a direct cause-and-effect relationship, mammary stromal fibroblasts (MSFs) were prepared from Cav-1−/− null mice and subjected to phenotypic analysis. Here, we provide evidence that Cav-1−/− MSFs share many characteristics with human cancer-associated fibroblasts. The Cav-1−/− MSF transcriptome significantly overlaps with human cancer-associated fibroblasts; both show a nearly identical profile of RB/E2F-regulated genes that are up-regulated, which is consistent with RB inactivation. This Cav-1−/− MSF gene signature is predictive of poor clinical outcome in breast cancer patients treated with tamoxifen. Consistent with these findings, Cav-1−/− MSFs show RB hyperphosphorylation and the up-regulation of estrogen receptor co-activator genes. We also evaluated the paracrine effects of “conditioned media” prepared from Cav-1−/− MSFs on wild-type mammary epithelia. Our results indicate that Cav-1−/− MSF “conditioned media” is sufficient to induce an epithelial-mesenchymal transition, indicative of an invasive phenotype. Proteomic analysis of this “conditioned media” reveals increased levels of proliferative/angiogenic growth factors. Consistent with these findings, Cav-1−/− MSFs are able to undergo endothelial-like transdifferentiation. Thus, these results have important implications for understanding the role of cancer-associated fibroblasts and RB inactivation in promoting tumor angiogenesis

Topics: Regular Articles
Publisher: American Society for Investigative Pathology
OAI identifier: oai:pubmedcentral.nih.gov:2665737
Provided by: PubMed Central
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