| First Author | Hsu I | Year | 2014 |
| Journal | Carcinogenesis | Volume | 35 |
| Issue | 3 | Pages | 651-61 |
| PubMed ID | 24148819 | Mgi Jnum | J:206524 |
| Mgi Id | MGI:5551338 | Doi | 10.1093/carcin/bgt348 |
| Citation | Hsu I, et al. (2014) Suppression of ERbeta signaling via ERbeta knockout or antagonist protects against bladder cancer development. Carcinogenesis 35(3):651-61 |
| abstractText | 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 (ERalpha) and estrogen receptor beta (ERbeta), 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 ERbeta plays a positive role in promoting BCa progression. Knockdown of ERbeta with ERbeta-shRNA in ERbeta-positive human BCa J82, 647v and T24 cell lines led to suppressed cell growth and invasion. Mice lacking ERbeta 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 ERbeta knockdown are more resistant to carcinogen-induced malignant transformation. Mechanism dissection found that targeting ERbeta 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 ERbeta knockdown-mediated growth reduction. Supportively, treating cells with the ERbeta-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 ERbeta could play positive roles in promoting BCa progression via MCM5 regulation. Targeting ERbeta through ERbeta-shRNA, PHTPP or via downstream targets, such as MCM5, could serve as potential therapeutic approaches to battle BCa. |
