Abstract
Urothelial carcinoma (UC) of the bladder is approximately three times more common in men than women. While the etiology for this gender difference in incidence remains unknown, a role for androgen receptor (AR) signaling has been suggested. The mechanisms by which AR activity is regulated in UC cells, however, are largely elusive. Here, we explore the significance of coregulators that are critical for the formation of a functional AR transcriptional complex, in UC cells. Using two AR-positive UC cell lines, TCC-SUP and UMUC3, we demonstrate the expression of the coactivators NCOA1, NCOA2, NCOA3, CREBBP, and EP300 in UC cells. small interfering RNA-mediated knockdown of the AR or any of these coactivators markedly impacted cell viability and abrogated androgen-dependent cell proliferation. Noteworthy, contrary to AR-positive prostate cancer cells, expression of these AR-associated coactivators was not androgen regulated in UC cells. To assess the clinical relevance of coactivator expression, we performed immunohistochemistry on paraffin-embedded sections from 55 patients with UC of the bladder. We found that while 24 out of 55 (44%) of tumors expressed the AR, each of the coactivators was expressed by 85-100% of the bladder cancers. Moreover, we noted a significant downregulation of NCOA1 expression in tumors versus adjacent, non-tumor bladder urothelium, with a mean of 68% (range 0-100) of tumor cells demonstrating NCOA1 staining versus a mean of 81% (range 0-90) of non-tumor cells (P=0.03). Taken together, our data suggest an important role for AR-associated coactivators in UC and point toward differences in the regulation of AR activity between bladder and prostate cancer cells.