Research Papers:

Estrogen Receptor Alpha Prevents Bladder Cancer Development via INPP4B inhibited Akt Pathway in vitro and in vivo

Iawen Hsu, Chiuan-Ren Yeh, Spencer Slavin, Hiroshi Miyamoto, George Netto, Yu-Chieh Tsai, Mesut Muyan, Xue-Ru Wu and Shuyuan Yeh _

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Oncotarget. 2014; 5:7917-7935. https://doi.org/10.18632/oncotarget.1421

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Iawen Hsu1*, Chiuan-Ren Yeh1*, Spencer Slavin1, Hiroshi Miyamoto2, George J. Netto2, Yu- Chieh Tsai1, Mesut Muyan3, Xue-Ru Wu4, Edward M. Messing1, Elizabeth A. Guancial5, Shuyuan Yeh1

1 Departments of Urology and Pathology, University of Rochester Medical Center, Rochester, NY 14642.

2 Departments of Pathology, Urology, and Oncology, The Johns Hopkins Hospital, Baltimore, MD 21231.

3 Department of Biochemistry & Biophysics, University of Rochester Medical Center, Rochester, NY 14642.

4 Department of Urology, New York University, School of Medicine, NY 10016.

5 Departments of Hematology and Oncology, University of Rochester Medical Center, Rochester, NY 14642.

* Contributed equally

Correspondence to:

Dr. Shuyuan Yeh, e-mail: [email protected]

Received: September 17, 2013     Accepted: July 07, 2014     Published: July 29, 2014

Abbreviations: ERα, estrogen receptor alpha; ERαKO, ERα knockout mice; BCa, bladder cancer; BBN, N-butyl-N-(4-hydroxybutyl) nitrosamine; IHC, immunohistochemistry; INPP4B, Inositol polyphosphate-4-phosphatase type II; MTT, 3-(4,5- Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide; MCA, 3-methylcholanthrene; WT, wild type.


Clinical reports show males have a higher bladder cancer (BCa) incidence than females. The sexual difference of BCa occurrence suggests that estrogen and its receptors may affect BCa development. Estrogen receptor alpha (ERα) is the classic receptor to convey estrogen signaling, however, the function of ERα in BCa development remains largely unknown. To understand the in vivo role of ERα in BCa development, we generated total and urothelial specific ERα knockout mice (ERαKO) and used the pre- carcinogen BBN to induce BCa. Earlier reports showed that ERα promotes breast and ovarian cancers in females. Surprisingly and of clinical importance, our results showed that ERα inhibits BCa development and loss of the ERα gene results in an earlier onset and higher incidence of BBN-induced in vivo mouse BCa. Supportively, carcinogen induced malignant transformation ability was reduced in ERα expressing urothelial cells as compared to ERα negative cells. Mechanism studies suggest that ERα could control the expression of INPP4B to reduce AKT activity and consequently reduce BCa cell growth. In addition, IHC staining of clinical sample analyses show that INPP4B expression, in correlation with reduced ERα, is significantly reduced in human BCa specimens. Together, this is the first report using the in vivo cre-loxP gene knockout mouse model to characterize ERα roles in BCa development. Our studies provide multiple in vitro cell studies and in vivo animal model data as well as human BCa tissue analyses to prove ERα plays a protective role in BCa initiation and growth at least partly via modulating the INPP4B/Akt pathway.

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