title: Caveolin-1-/- null mammary stromal fibroblasts share characteristics with human breast cancer-associated fibroblasts.
abstract: Recently, we reported that human breast cancer-associated fibroblasts show functional inactivation of the retinoblastoma (RB) tumor suppressor and down-regulation of caveolin-1 (Cav-1) protein expression. However, it remains unknown whether loss of Cav-1 is sufficient to confer functional RB inactivation in mammary fibroblasts. To establish a direct cause-and-effect relationship, mammary stromal fibroblasts (MSFs) were prepared from Cav-1(-/-) null mice and subjected to phenotypic analysis. Here, we provide evidence that Cav-1(-/-) MSFs share many characteristics with human cancer-associated fibroblasts. The Cav-1(-/-) MSF transcriptome significantly overlaps with human cancer-associated fibroblasts; both show a nearly identical profile of RB/E2F-regulated genes that are up-regulated, which is consistent with RB inactivation. This Cav-1(-/-) MSF gene signature is predictive of poor clinical outcome in breast cancer patients treated with tamoxifen. Consistent with these findings, Cav-1(-/-) MSFs show RB hyperphosphorylation and the up-regulation of estrogen receptor co-activator genes. We also evaluated the paracrine effects of "conditioned media" prepared from Cav-1(-/-) MSFs on wild-type mammary epithelia. Our results indicate that Cav-1(-/-) MSF "conditioned media" is sufficient to induce an epithelial-mesenchymal transition, indicative of an invasive phenotype. Proteomic analysis of this "conditioned media" reveals increased levels of proliferative/angiogenic growth factors. Consistent with these findings, Cav-1(-/-) MSFs are able to undergo endothelial-like transdifferentiation. Thus, these results have important implications for understanding the role of cancer-associated fibroblasts and RB inactivation in promoting tumor angiogenesis.
authors.affiliation: Department of Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University, 233 South 10 Street, Philadelphia, PA 19107, USA. federica.sotgia@jefferson.edu
authors.forename: Federica
authors.initials: F
authors.lastname: Sotgia
authors.forename: Francesco
authors.initials: F
authors.lastname: Del Galdo
authors.forename: Mathew C
authors.initials: MC
authors.lastname: Casimiro
authors.forename: Gloria
authors.initials: G
authors.lastname: Bonuccelli
authors.forename: Isabelle
authors.initials: I
authors.lastname: Mercier
authors.forename: Diana
authors.initials: D
authors.lastname: Whitaker-Menezes
authors.forename: Kristin M
authors.initials: KM
authors.lastname: Daumer
authors.forename: Jie
authors.initials: J
authors.lastname: Zhou
authors.forename: Chenguang
authors.initials: C
authors.lastname: Wang
authors.forename: Sanjay
authors.initials: S
authors.lastname: Katiyar
authors.forename: Huan
authors.initials: H
authors.lastname: Xu
authors.forename: Emily
authors.initials: E
authors.lastname: Bosco
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Quong
authors.forename: Bruce
authors.initials: B
authors.lastname: Aronow
authors.forename: Agnieszka K
authors.initials: AK
authors.lastname: Witkiewicz
authors.forename: Carlo
authors.initials: C
authors.lastname: Minetti
authors.forename: Philippe G
authors.initials: PG
authors.lastname: Frank
authors.forename: Sergio A
authors.initials: SA
authors.lastname: Jimenez
authors.forename: Erik S
authors.initials: ES
authors.lastname: Knudsen
authors.forename: Richard G
authors.initials: RG
authors.lastname: Pestell
authors.forename: Michael P
authors.initials: MP
authors.lastname: Lisanti
mesh_terms: D015153:Blotting, Western; D001940:Breast / Q000166:cytology / Q000502:physiology; D001943:Breast Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D051242:Caveolin 1 / Q000172:deficiency* / Q000235:genetics*; D018929:Cell Culture Techniques; D002455:Cell Division; D018450:Disease Progression; D018572:Disease-Free Survival; D004847:Epithelial Cells / Q000166:cytology / Q000473:pathology / Q000502:physiology; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000473:pathology* / Q000502:physiology; D006801:Humans; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics; D017154:Stromal Cells / Q000166:cytology / Q000473:pathology* / Q000502:physiology; D016019:Survival Analysis
chemical_list: C495540:CAV1 protein, human; D051242:Caveolin 1; D012333:RNA, Messenger; D012334:RNA, Neoplasm