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Research Paper
Human breast cancer-associated fibroblasts (CAFs) show caveolin-1 down-regulation and RB tumor suppressor functional inactivation: Implications for the response to hormonal therapy
Isabelle Mercier, Mathew C. Casimiro, Chenguang Wang, Anne L. Rosenberg, Judy Quong, Alimatou Minkeu, Kathleen G. Allen, Christiane Danilo, Federica Sotgia, Gloria Bonuccelli, Jean-François Jasmin, Huan Xu, Emily Bosco, Bruce Aronow, Agnieszka Witkiewicz, Richard G. Pestell, Erik S. Knudsen and Michael P. Lisanti
volume 7 | issue 8
August 2008Subscribe to this journal for $129/year
It is becoming increasingly apparent that the tumor micro-environment plays a critical role in human breast cancer onset and progression. Therefore, we isolated cancer-associated fibroblasts (CAFs) from human breast cancer lesions and studied their properties, as compared with normal mammary fibroblasts (NFs) isolated from the same patient. Here, we demonstrate that 8 out of 11 CAFs show dramatic down-regulation of caveolin-1 (Cav-1) protein expression; Cav-1 is a well-established marker that is normally decreased during the oncogenic transformation of fibroblasts. Next, we performed gene expression profiling studies (DNA mircoarray) and established a CAF gene expression signature. Interestingly, the expression signature associated with CAFs encompasses a large number of genes that are regulated via the RB-pathway. The CAF gene signature is also predictive of poor clinical outcome in breast cancer patients that were treated with tamoxifen mono-therapy, indicating that CAFs may be useful for predicting the response to hormonal therapy. Finally, we show that replacement of Cav-1 expression in CAFs (using a cell-permeable peptide approach) is sufficient to revert their hyper-proliferative phenotype and prevent RB hyper-phosphorylation. Taken together, these studies highlight the critical role of Cav-1 down-regulation in maintaining the abnormal phenotype of human breast cancer-associated fibroblasts.