TY - JOUR
T1 - Caveolin-1-/- null mammary stromal fibroblasts share characteristics with human breast cancer-associated fibroblasts
AU - Sotgia, Federica
AU - Del Galdo, Francesco
AU - Casimiro, Mathew C.
AU - Bonuccelli, Gloria
AU - Mercier, Isabelle
AU - Whitaker-Menezes, Diana
AU - Daumer, Kristin M.
AU - Zhou, Jie
AU - Wang, Chenguang
AU - Katiyar, Sanjay
AU - Xu, Huan
AU - Bosco, Emily
AU - Quong, Andrew A.
AU - Aronow, Bruce
AU - Witkiewicz, Agnieszka K.
AU - Minetti, Carlo
AU - Frank, Philippe G.
AU - Jimenez, Sergio A.
AU - Knudsen, Erik S.
AU - Pestell, Richard G.
AU - Lisanti, Michael P.
N1 - Funding Information:
Supported by grants from the Elsa U. Pardee Foundation and the W.W. Smith Charitable Trust, and a Research Scholar Grant from the American Cancer Society to F.S. I.M. was supported by a Post-doctoral Fellowship from the Susan G. Komen Breast Cancer Foundation. P.G.F. was supported by a grant from the W.W. Smith Charitable Trust, and a Career Catalyst Award from the Susan G. Komen Breast Cancer Foundation. M.P.L. was supported by grants from the NIH/NCI ( R01-CA-80250; R01-CA-098779; R01-CA-120876 ), the American Association for Cancer Research, and the Department of Defense-Breast Cancer Research Program (Synergistic Idea Award). This project is funded, in part, under a grant with the Pennsylvania Department of Health (to F.S. and M.P.L.). R.G.P. was supported by grants from the NIH/NCI ( R01-CA-70896, R01-CA-75503, R01-CA-86072, and R01-CA-107382 ) and the Dr. Ralph and Marian C. Falk Medical Research Trust. The Kimmel Cancer Center was supported by the NIH/NCI Cancer Center Core grant P30-CA-56036 (to R.G.P.).
PY - 2009/3
Y1 - 2009/3
N2 - 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.
AB - 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.
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U2 - 10.2353/ajpath.2009.080658
DO - 10.2353/ajpath.2009.080658
M3 - Article
C2 - 19234134
AN - SCOPUS:62549120295
SN - 0002-9440
VL - 174
SP - 746
EP - 761
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 3
ER -