title: Human breast cancer-associated fibroblasts (CAFs) show caveolin-1 downregulation and RB tumor suppressor functional inactivation: Implications for the response to hormonal therapy.
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.
authors.affiliation: Kimmel Cancer Center, Department of Cancer Biology and Medical Oncology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Mercier
authors.forename: Mathew C
authors.initials: MC
authors.lastname: Casimiro
authors.forename: Chenguang
authors.initials: C
authors.lastname: Wang
authors.forename: Anne L
authors.initials: AL
authors.lastname: Rosenberg
authors.forename: Judy
authors.initials: J
authors.lastname: Quong
authors.forename: Alimatou
authors.initials: A
authors.lastname: Minkeu
authors.forename: Kathleen G
authors.initials: KG
authors.lastname: Allen
authors.forename: Christiane
authors.initials: C
authors.lastname: Danilo
authors.forename: Federica
authors.initials: F
authors.lastname: Sotgia
authors.forename: Gloria
authors.initials: G
authors.lastname: Bonuccelli
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Jasmin
authors.forename: Huan
authors.initials: H
authors.lastname: Xu
authors.forename: Emily
authors.initials: E
authors.lastname: Bosco
authors.forename: Bruce
authors.initials: B
authors.lastname: Aronow
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Witkiewicz
authors.forename: Richard G
authors.initials: RG
authors.lastname: Pestell
authors.forename: Erik S
authors.initials: ES
authors.lastname: Knudsen
authors.forename: Michael P
authors.initials: MP
authors.lastname: Lisanti
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D051242:Caveolin 1 / Q000235:genetics* / Q000378:metabolism; D002478:Cells, Cultured; D015536:Down-Regulation; D005260:Female; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D006801:Humans; D008957:Models, Genetic; D016160:Retinoblastoma Protein / Q000235:genetics* / Q000378:metabolism
chemical_list: D051242:Caveolin 1; D016160:Retinoblastoma Protein