MP52-13 ESTROGEN RECEPTOR α IN CANCER ASSOCIATED FIBROBLASTS SUPPRESSES PROSTATE CANCER INVASION VIA MODULATION OF THROMBOSPONDIN-2 AND MATRIX METALLOPROTEINASE 3

Abstract

You have accessJournal of UrologyProstate Cancer: Basic Research V1 Apr 2014MP52-13 ESTROGEN RECEPTOR α IN CANCER ASSOCIATED FIBROBLASTS SUPPRESSES PROSTATE CANCER INVASION VIA MODULATION OF THROMBOSPONDIN-2 AND MATRIX METALLOPROTEINASE 3 Chiuan-Ren Yeh, Spencer Slavin, Jun Da, Chawnshang Chang, Edward M. Messing, Hiroshi Miyamoto, and Shuyuan Yeh Chiuan-Ren YehChiuan-Ren Yeh More articles by this author , Spencer SlavinSpencer Slavin More articles by this author , Jun DaJun Da More articles by this author , Chawnshang ChangChawnshang Chang More articles by this author , Edward M. MessingEdward M. Messing More articles by this author , Hiroshi MiyamotoHiroshi Miyamoto More articles by this author , and Shuyuan YehShuyuan Yeh More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2014.02.1623AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail Introduction and Objectives The prostate cancer (PCa) microenvironment contains active stromal cells known as cancer associated fibroblasts (CAF) that may play important roles in influencing tumor progression. Here we studied the CAF Estrogen receptor α (ERα)’s role and found it could protect against PCa invasion. Methods (1) Human tissue sample IHC staining to analyze the correlation of ERα expression and recurrent free survival in PCa. (2) Lentiviral ERα transduction of CAF cells and firefly luciferase infection of 22Rv1. (3) Zymography was used to determine MMP3 and MMP2 activities.(4) Chromatin immunoprecipitation (ChIP) assay was used to determine the ERα binding to target gene (5) Q-PCR analysis was performedto detect mRNA expression. Results Immunohistochemistry on prostatectomy specimens showed that PCa patients with ERα-positive stroma had a significantly lower risk for biochemical recurrence. In vitro invasion assays further confirmed that the stromal ERα was able to reduce PCa cell invasion. Dissection of the molecular mechanism revealed that the CAF ERα could function through a CAF-epithelial interaction via selectively up-regulating thrombospondin-2 (Thbs2) and down-regulating matrix metalloproteinase 3 (MMP3) at the protein and mRNA levels. Chromatin Immunoprecipitation assays further showed that ERα could bind to an estrogen response element (ERE) on the promoter of Thbs2. Importantly, knockdown of Thbs2 led to increased MMP3 expression and interruption of the ERα mediated invasion suppression providing further evidence of an ERα-Thbs2-MMP3 axis in CAF. In vivo studies using athymic nude mice injected with 22Rv1 PCa epithelial cells and CAF cells ± ERα also confirmed that mice co-implanted with PCa cells and CAF ERα+ cells had less tumor foci in the pelvic lymph nodes, less metastasis, and tumors showed less angiogenesis, MMP3, and MMP9 (an MMP3 downstream target) positive staining. Conclusions Together, these data suggest that CAF ERα could play protective roles in suppressing PCa metastasis. Our results may lead to developing new and alternative therapeutic approaches to battle PCa via controlling ERα signaling in CAF. © 2014FiguresReferencesRelatedDetails Volume 191Issue 4SApril 2014Page: e584 Advertisement Copyright & Permissions© 2014MetricsAuthor Information Chiuan-Ren Yeh More articles by this author Spencer Slavin More articles by this author Jun Da More articles by this author Chawnshang Chang More articles by this author Edward M. Messing More articles by this author Hiroshi Miyamoto More articles by this author Shuyuan Yeh More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...