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 journalArticle

107 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1212-1225
Number of pages14
JournalCancer Biology and Therapy
Volume7
Issue number8
DOIs
StatePublished - Aug 2008

Keywords

  • Caveolin-1
  • Invasive breast cancer
  • Mammary fibroblasts

ASJC Scopus subject areas

  • Molecular Medicine
  • Oncology
  • Pharmacology
  • Cancer Research

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

    Mercier, I., Casimiro, M. C., Wang, C., Rosenberg, A. L., Quong, J., Minkeu, A., Allen, K. G., Danilo, C., Sotgia, F., Bonuccelli, G., Jasmin, J. F., Xu, H., Bosco, E., Aronow, B., Witkiewicz, A., Pestell, R. G., Knudsen, E. S., & Lisanti, M. P. (2008). Human breast cancer-associated fibroblasts (CAFs) show caveolin-1 downregulation and RB tumor suppressor functional inactivation: Implications for the response to hormonal therapy. Cancer Biology and Therapy, 7(8), 1212-1225. https://doi.org/10.4161/cbt.7.8.6220