title: Estrogen receptor α in cancer-associated fibroblasts suppresses prostate cancer invasion via modulation of thrombospondin 2 and matrix metalloproteinase 3.
abstract: 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 role of CAF estrogen receptor alpha (ERα) and found that it could protect against PCa invasion. 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 upregulating thrombospondin 2 (Thbs2) and downregulating matrix metalloproteinase 3 (MMP3) at the protein and messenger RNA levels. Chromatin immunoprecipitation assays further showed that ERα could bind to an estrogen response element 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 CWR22Rv1 (22Rv1) PCa epithelial cells and CAF cells ± ERα also confirmed that mice coimplanted with PCa cells and CAF ERα+ cells had less tumor foci in the pelvic lymph nodes, less metastases, and tumors showed less angiogenesis, MMP3, and MMP9 (an MMP3 downstream target) positive staining. 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.
authors.affiliation: Departments of Urology and Pathology, University of Rochester Medical Center Rochester, 601 Elmwood Avenue, NY 14642, USA.
authors.forename: Spencer
authors.initials: S
authors.lastname: Slavin
authors.affiliation: Departments of Urology and Pathology, University of Rochester Medical Center Rochester, 601 Elmwood Avenue, NY 14642, USA.
authors.forename: Chiuan-Ren
authors.initials: CR
authors.lastname: Yeh
authors.affiliation: Departments of Urology and Pathology, University of Rochester Medical Center Rochester, 601 Elmwood Avenue, NY 14642, USA, Department of Urology, Shanghai Jaotong University, Shanghai, China and.
authors.forename: Jun
authors.initials: J
authors.lastname: Da
authors.affiliation: Departments of Urology and Pathology, University of Rochester Medical Center Rochester, 601 Elmwood Avenue, NY 14642, USA.
authors.forename: Shengqiang
authors.initials: S
authors.lastname: Yu
authors.affiliation: Departments of Urology and Pathology, University of Rochester Medical Center Rochester, 601 Elmwood Avenue, NY 14642, USA.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Miyamoto
authors.affiliation: Departments of Urology and Pathology, University of Rochester Medical Center Rochester, 601 Elmwood Avenue, NY 14642, USA.
authors.forename: Edward M
authors.initials: EM
authors.lastname: Messing
authors.affiliation: Departments of Hematology and Oncology, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Guancial
authors.affiliation: Departments of Urology and Pathology, University of Rochester Medical Center Rochester, 601 Elmwood Avenue, NY 14642, USA, Shuyuan_Yeh@urmc.rochester.edu.
authors.forename: Shuyuan
authors.initials: S
authors.lastname: Yeh
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology*; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D064593:Heterografts; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D019278:Matrix Metalloproteinase 3 / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D010641:Phenotype; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology*; D011485:Protein Binding; D034622:RNA Interference; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology; D019699:Thrombospondins / Q000235:genetics / Q000378:metabolism*; D000099262:Thrombospondin 2
chemical_list: D047628:Estrogen Receptor alpha; D019278:Matrix Metalloproteinase 3; D019699:Thrombospondins; D000099262:Thrombospondin 2