Caveolin-1-/- null mammary stromal fibroblasts share characteristics with human breast cancer-associated fibroblasts.
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.
Sotgia
Federica
F
Department of Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University, 233 South 10 Street, Philadelphia, PA 19107, USA. federica.sotgia@jefferson.edu
Del Galdo
Francesco
F
Casimiro
Mathew C
MC
Bonuccelli
Gloria
G
Mercier
Isabelle
I
Whitaker-Menezes
Diana
D
Daumer
Kristin M
KM
Zhou
Jie
J
Wang
Chenguang
C
Katiyar
Sanjay
S
Xu
Huan
H
Bosco
Emily
E
Quong
Andrew A
AA
Aronow
Bruce
B
Witkiewicz
Agnieszka K
AK
Minetti
Carlo
C
Frank
Philippe G
PG
Jimenez
Sergio A
SA
Knudsen
Erik S
ES
Pestell
Richard G
RG
Lisanti
Michael P
MP
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
C495540:CAV1 protein, human; D051242:Caveolin 1; D012333:RNA, Messenger; D012334:RNA, Neoplasm