Estrogen receptor ? 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 (ER?) and found that it could protect against PCa invasion. Immunohistochemistry on prostatectomy specimens showed that PCa patients with ER?-positive stroma had a significantly lower risk for biochemical recurrence. In vitro invasion assays further confirmed that the stromal ER? was able to reduce PCa cell invasion. Dissection of the molecular mechanism revealed that the CAF ER? 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 ER? 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 ER? mediated invasion suppression, providing further evidence of an ER?-Thbs2-MMP3 axis in CAF. In vivo studies using athymic nude mice injected with CWR22Rv1 (22Rv1) PCa epithelial cells and CAF cells ± ER? also confirmed that mice coimplanted with PCa cells and CAF ER?+ 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 ER? could play protective roles in suppressing PCa metastasis. Our results may lead to developing new and alternative therapeutic approaches to battle PCa via controlling ER? signaling in CAF.

SUBMITTER: Slavin S 

PROVIDER: S-EPMC4043239 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature