Abstract
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.
Highlights
Urothelial carcinoma of the bladder is the fourth most common cancer in men and eleventh most common cancer in women in the United States [1]
Our studies provide multiple in vitro cell studies and in vivo animal model data as well as human bladder cancer (BCa) tissue analyses to prove estrogen receptor alpha (ERα) plays a protective role in BCa initiation and growth at least partly via modulating the Inositol polyphosphate-4-phosphatase type II (INPP4B)/Akt pathway
There are no available data concerning ERα mRNA level differences between normal and BCa tissue, and Immunohistochemical staining (IHC) staining results of ERα protein expression could be compromised by the antibody specificity, or the method and time of tissue fixation [17, 18]
Summary
Urothelial carcinoma of the bladder is the fourth most common cancer in men and eleventh most common cancer in women in the United States [1]. It has been reported that BCa has the highest lifetime treatment cost per patient among all types of solid cancers [2], and most therapies for BCa patients will eventually fail. It is critical to understand the underlying mechanisms and find an approach to manage BCa development. Environmental chemical exposure, and infectious parasites were found to be associated with higher BCa risks. BCa incidence for males to females is 3.5 to 1 [3], suggesting sex hormone signals may play a role in the occurrence of BCa. Supportively, evidence suggests androgens/androgen receptor (AR) promote BCa www.impactjournals.com/oncotarget development [4]. Evidence suggests androgens/androgen receptor (AR) promote BCa www.impactjournals.com/oncotarget development [4] It remains unclear whether estrogen and estrogen receptors (ERs) play roles in the BCa occurrence
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