Human breast cancer-associated fibroblasts (CAFs) show caveolin-1 downregulation 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, Michael P. Lisanti

    Research output: Contribution to journalArticlepeer-review

    Abstract

    It is becoming increasingly apparent that the tumor microenvironment 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 downregulation 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 microarray) 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 downregulation in maintaining the abnormal phenotype of human breast cancer-associated fibroblasts. ©2008 Landes Bioscience.
    Original languageEnglish
    Pages (from-to)1212-1225
    Number of pages13
    JournalCancer Biology and Therapy
    Volume7
    Issue number8
    DOIs
    Publication statusPublished - Aug 2008

    Keywords

    • Caveolin-1
    • Invasive breast cancer
    • Mammary fibroblasts

    Fingerprint

    Dive into the research topics of 'Human breast cancer-associated fibroblasts (CAFs) show caveolin-1 downregulation and RB tumor suppressor functional inactivation: Implications for the response to hormonal therapy'. Together they form a unique fingerprint.

    Cite this