Suppression of ERβ signaling via ERβ knockout or antagonist protects against bladder cancer development

Abstract

Epidemiological studies showed that women have a lower bladder cancer (BCa) incidence, yet higher muscle-invasive rates than men, suggesting that estrogen and the estrogen receptors, estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ), may play critical roles in BCa progression. Using in vitro cell lines and an in vivo carcinogen N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN)-induced mouse BCa model, we found that ERβ plays a positive role in promoting BCa progression. Knockdown of ERβ with ERβ-shRNA in ERβ-positive human BCa J82, 647v and T24 cell lines led to suppressed cell growth and invasion. Mice lacking ERβ have less cancer incidence with reduced expression of the proliferation marker Ki67 in BBN-induced BCa. Consistently, our results show that non-malignant urothelial cells with ERβ knockdown are more resistant to carcinogen-induced malignant transformation. Mechanism dissection found that targeting ERβ suppressed the expression of minichromosome maintenance complex component 5 (MCM5), a DNA replication licensing factor that is involved in tumor cell growth. Restoring MCM5 expression can partially reverse ERβ knockdown-mediated growth reduction. Supportively, treating cells with the ERβ-specific antagonist, 4-[2-Phenyl-5,7-bis(trifluoromethyl) pyrazolo[1,5-a]pyrimidin-3-yl]phenol (PHTPP), reduced BCa cell growth and invasion, as well as MCM5 expression. Furthermore, we provide the first evidence that BCa burden and mortality can be controlled by PHTPP treatment in the carcinogen-induced BCa model. Together, these results demonstrate that ERβ could play positive roles in promoting BCa progression via MCM5 regulation. Targeting ERβ through ERβ-shRNA, PHTPP or via downstream targets, such as MCM5, could serve as potential therapeutic approaches to battle BCa.

Gender differences in incidence and outcomes of urothelial and kidney cancer

“…48 However, some data suggest expression of this receptor could promote bladder cancer progres sion. In in vitro and in vivo experiments, Hsu et al 49 showed that ERβ knockdown in nonmalignant urothe lial cells conferred resistance to 3methylcholanthrene induced malignant transformation. These authors also showed that ERβdeficient mice were less susceptible to BNNinduced bladder cancer than their wildtype counter parts.…”

The Estrogen Pathway: Estrogen Receptor-α, Progesterone Receptor, and Estrogen Receptor-β Expression in Radical Cystectomy Urothelial Cell Carcinoma Specimens

“…Knockdown of ER-b expression in both in vitro ER-bepositive human bladder cancer cell lines and in vivo carcinogen (N-butyl-N-(4-hydroxybutyl) nitrosamine)-induced mouse BC model resulted in suppression of cell growth and invasion, as well as decreased expression of Ki 67 (proliferation marker). 35 Furthermore, treatment of the cell lines with the ERbespecific antagonist PHTPP decreased cell growth and invasion, suggesting that ER-b may serve as a potential therapeutic target.…”

Estrogen Receptor-α is a Key Mediator and Therapeutic Target for Bladder Complications of Benign Prostatic Hyperplasia

“…This is in agreement with other investigations that did not find bladder hypertrophy or histologic changes in untreated ERαKO or ERβKO mice. 22,23 We did not observe bladder enlargement in ERαKO male mice treated with T+E 2 , indicating that ERα is necessary for hormone-induced bladder enlargement. While the specific cell types and target tissues mediating this effect remain unknown, bladder outlet obstruction is related to prostatic enlargement in male mice treated with T+E 2 , and the bladder responds with hypertrophy and eventually decompensates.…”