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

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.

Gender differences in incidence and outcomes of urothelial and kidney cancer

“…In in vivo studies, ERαknockout female and male mice seem to have earlier disease development and a higher incidence of BNN induced bladder cancer than mice expressing ERα. 47 The role of ERβ in bladder cancer development is still unclear; some data have suggested ERβ might be protec tive in patients with bladder cancer, as its expression has been found to be associated with better RFS for patients with NMIBC. 48 However, some data suggest expression of this receptor could promote bladder cancer progres sion.…”

INPP4B overexpression suppresses migration, invasion and angiogenesis of human prostate cancer cells

“…INPP4B was believed to inhibit the activity of Akt through the turnover of PI(3,4)P, and several reports have demonstrated the interaction between INPP4B and Akt signalling . Akt transmits angiogenic and oncogenic signals and can directly induce angiogenesis .…”

“…INPP4B is a tumour suppressor that controls the levels of PI3K lipid products and is potentially targetable in aggressive human thyroid cancers, hepatocellular carcinoma, breast cancer, bladder cancer and others. Moreover, INPP4B suppresses PC3 cell invasion .…”

The impact of female gender on bladder cancer-specific death risk after radical cystectomy: a meta-analysis of 27,912 patients

“…By knockout ERα in mice, the cancer incidence increased in BBN-induced bladder cancer model. Further mechanism study unveiled ERα plays a protective role via modulating the INPP4B/Akt pathway [34]. By knockout ERβ in mice, cancer progression was suppressed in BBNinduced bladder cancer model.…”