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

102 Citations (Scopus)

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
StatePublished - Aug 2008

Fingerprint

Caveolin 1
Down-Regulation
Breast Neoplasms
Neoplasms
Therapeutics
Fibroblasts
Caveolins
Phenotype
Tumor Microenvironment
Cancer-Associated Fibroblasts
Gene Expression Profiling
Tamoxifen
Oligonucleotide Array Sequence Analysis
Transcriptome
Genes
Breast
Phosphorylation
Peptides

Keywords

  • Caveolin-1
  • Invasive breast cancer
  • Mammary fibroblasts

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Human breast cancer-associated fibroblasts (CAFs) show caveolin-1 downregulation and RB tumor suppressor functional inactivation : Implications for the response to hormonal therapy. / Mercier, Isabelle; Casimiro, Mathew C.; Wang, Chenguang; Rosenberg, Anne L.; Quong, Judy; Minkeu, Alimatou; Allen, Kathleen G.; Danilo, Christiane; Sotgia, Federica; Bonuccelli, Gloria; Jasmin, Jean François; Xu, Huan; Bosco, Emily; Aronow, Bruce; Witkiewicz, Agnieszka; Pestell, Richard G.; Knudsen, Erik S.; Lisanti, Michael P.

In: Cancer Biology and Therapy, Vol. 7, No. 8, 08.2008, p. 1212-1225.

Research output: Contribution to journalArticle

Mercier, I, Casimiro, MC, Wang, C, Rosenberg, AL, Quong, J, Minkeu, A, Allen, KG, Danilo, C, Sotgia, F, Bonuccelli, G, Jasmin, JF, Xu, H, Bosco, E, Aronow, B, Witkiewicz, A, Pestell, RG, Knudsen, ES & Lisanti, MP 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, vol. 7, no. 8, pp. 1212-1225.
Mercier, Isabelle ; Casimiro, Mathew C. ; Wang, Chenguang ; Rosenberg, Anne L. ; Quong, Judy ; Minkeu, Alimatou ; Allen, Kathleen G. ; Danilo, Christiane ; Sotgia, Federica ; Bonuccelli, Gloria ; Jasmin, Jean François ; Xu, Huan ; Bosco, Emily ; Aronow, Bruce ; Witkiewicz, Agnieszka ; Pestell, Richard G. ; Knudsen, Erik S. ; Lisanti, Michael P. / Human breast cancer-associated fibroblasts (CAFs) show caveolin-1 downregulation and RB tumor suppressor functional inactivation : Implications for the response to hormonal therapy. In: Cancer Biology and Therapy. 2008 ; Vol. 7, No. 8. pp. 1212-1225.
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AU - Wang, Chenguang

AU - Rosenberg, Anne L.

AU - Quong, Judy

AU - Minkeu, Alimatou

AU - Allen, Kathleen G.

AU - Danilo, Christiane

AU - Sotgia, Federica

AU - Bonuccelli, Gloria

AU - Jasmin, Jean François

AU - Xu, Huan

AU - Bosco, Emily

AU - Aronow, Bruce

AU - Witkiewicz, Agnieszka

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AU - Knudsen, Erik S.

AU - Lisanti, Michael P.

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