Caveolin-1-/- Null Mammary Stromal Fibroblasts Share Characteristics with Human Breast Cancer-Associated Fibroblasts

被引：114

作者：

Sotgia, Federica ^{[1
,3
,5
]}

Del Galdo, Francesco ^{[2
]}

Casimiro, Mathew C. ^{[1
,3
]}

Bonuccelli, Gloria ^{[1
,3
]}

Mercier, Isabelle ^{[1
,3
]}

Whitaker-Menezes, Diana ^{[1
,3
]}

Daumer, Kristin M. ^{[1
,3
]}

Zhou, Jie ^{[1
,3
]}

Wang, Chenguang ^{[1
,3
]}

Katiyar, Sanjay ^{[1
,3
]}

Xu, Huan ^{[6
]}

Bosco, Emily ^{[6
]}

Quong, Andrew A. ^{[1
,3
]}

Aronow, Bruce ^{[6
]}

Witkiewicz, Agnieszka K. ^{[4
]}

Minetti, Carlo ^{[5
]}

Frank, Philippe G. ^{[1
,3
]}

Jimenez, Sergio A. ^{[2
]}

Knudsen, Erik S. ^{[1
,3
]}

Pestell, Richard G. ^{[1
,3
]}

Lisanti, Michael P. ^{[1
,3
,5
]}

机构：

[1] Thomas Jefferson Univ, Kimmel Canc Ctr, Dept Canc Biol & Med Oncol, Philadelphia, PA 19107 USA

[2] Thomas Jefferson Univ, Kimmel Canc Ctr, Dept Dermatol, Philadelphia, PA 19107 USA

[3] Thomas Jefferson Univ, Stem Cell Biol & Regenerat Med Ctr, Philadelphia, PA 19107 USA

[4] Thomas Jefferson Univ, Dept Pathol Anat & Cell Biol, Philadelphia, PA 19107 USA

[5] Univ Genoa, Muscular & Neurodegenerat Dis Unit, Genoa, Italy

[6] Cincinnati Childrens Hosp & Med Ctr, Cincinnati, OH USA

来源：

AMERICAN JOURNAL OF PATHOLOGY | 2009年 / 174卷 / 03期

关键词：

GENE-EXPRESSION SIGNATURE; GROWTH-FACTOR; ENDOSIALIN TEM1; STEM-CELLS; IN-VITRO; RESPONSIVENESS INVITRO; MESENCHYMAL TRANSITION; HORMONE RECEPTORS; EPITHELIAL-CELLS; TUMOR STROMA;

D O I：

10.2353/ajpath.2009.080658

中图分类号：

R36 [病理学];

学科分类号：

100104 ;

摘要：

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

引用

页码：746 / 761

页数：16

共 42 条

[1] Gene expression signature of estrogen receptor α status in breast cancer -: art. no. 37 [J].

Abba, MC ;

Hu, YH ;

Sun, HX ;

Drake, JA ;

Gaddis, S ;

Baggerly, K ;

Sahin, A ;

Aldaz, CM .

BMC GENOMICS, 2005, 6 (1)

[2] Endosialin/TEM 1/CD248 is a pericyte marker of embryonic and tumor neovascularization [J].

Bagley, Rebecca G. ;

Honma, Nakayuki ;

Weber, William ;

Boutin, Paula ;

Rouleau, Cecile ;

Shankara, Srinivas ;

Kataoka, Shiro ;

Ishida, Isao ;

Roberts, Bruce L. ;

Teicher, Beverly A. .

MICROVASCULAR RESEARCH, 2008, 76 (03) :180-188

[3] Human endothelial precursor cells express tumor endothelial marker 1/endosialin/CD248 [J].

Bagley, Rebecca G. ;

Rouleau, Cecile ;

St. Martin, Thia ;

Boutin, Paula ;

Weber, William ;

Ruzek, Melanie ;

Honma, Nakayuki ;

Nacht, Mariana ;

Shankara, Srinivas ;

Kataoka, Shiro ;

Ishida, Isao ;

Roberts, Bruce L. ;

Teicher, Beverly A. .

MOLECULAR CANCER THERAPEUTICS, 2008, 7 (08) :2536-2546

[4] Tumor stroma marker endosialin (Tem1) is a binding partner of metastasis-related protein Mac-2 BP/90K [J].

Becker, Renate ;

Lenter, Martin C. ;

Vollkommer, Tobias ;

Boos, Anja M. ;

Pfaff, Dennis ;

Augustin, Hellmut G. ;

Christian, Sven .

FASEB JOURNAL, 2008, 22 (08) :3059-3067

[5] An embryonic stem cell-like gene expression signature in poorly differentiated aggressive human tumors [J].

Ben-Porath, Ittai ;

Thomson, Matthew W. ;

Carey, Vincent J. ;

Ge, Ruping ;

Bell, George W. ;

Regev, Aviv ;

Weinberg, Robert A. .

NATURE GENETICS, 2008, 40 (05) :499-507

[6] The retinoblastoma tumor suppressor modifies the therapeutic response of breast cancer [J].

Bosco, Emily E. ;

Wang, Ying ;

Xu, Huan ;

Zilfou, Jack T. ;

Knudsen, Karen E. ;

Aronow, Bruce J. ;

Lowe, Scott W. ;

Knudsen, Erik S. .

JOURNAL OF CLINICAL INVESTIGATION, 2007, 117 (01) :218-228

[7] Absence of caveolin-1 sensitizes mouse skin to carcinogen-induced epidermal hyperplasia and tumor formation [J].

Capozza, F ;

Williams, TM ;

Schubert, W ;

McClain, S ;

Bouzahzah, B ;

Sotgia, F ;

Lisanti, MP .

AMERICAN JOURNAL OF PATHOLOGY, 2003, 162 (06) :2029-2039

[8] Enhancement of tumor invasion depends on transdifferentiation of skin fibroblasts mediated by reactive oxygen species [J].

Cat, Bahar ;

Stuhlmann, Dominik ;

Steinbrenner, Holger ;

Alili, Lirija ;

Holtkoetter, Olaf ;

Sies, Helmut ;

Brenneisen, Peter .

JOURNAL OF CELL SCIENCE, 2006, 119 (13) :2727-2738

[9] Endosialin (Tem1) is a marker of tumor-associated myofibroblasts and tumor vessel-associated mural cells [J].

Christian, Sven ;

Winkler, Renate ;

Helfrich, Iris ;

Boos, Anja M. ;

Besemfelder, Eva ;

Schadendorf, Dirk ;

Augustin, Hellmut G. .

AMERICAN JOURNAL OF PATHOLOGY, 2008, 172 (02) :486-494

[10] Genes regulated by estrogen in breast tumor cells in vitro are similarly regulated in vivo in tumor xenografts and human breast tumors [J].

Creighton, Chad J. ;

Cordero, Kevin E. ;

Larios, Jose M. ;

Miller, Rebecca S. ;

D Johnson, Michael ;

Chinnaiyan, Arul M. ;

Lippman, Marc E. ;

Rae, James M. .

GENOME BIOLOGY, 2006, 7 (04)

← 1 2 3 4 5 →