Document Type

Dissertation

Degree

Doctor of Philosophy (PhD)

Major/Program

Biochemistry

First Advisor's Name

Irina Agoulnik

First Advisor's Committee Title

Committee Chair

Second Advisor's Name

Yukching Tse Dinh

Second Advisor's Committee Title

Committee Member

Third Advisor's Name

Yuan Liu

Third Advisor's Committee Title

Committee Member

Fourth Advisor's Name

Jeffrey Boyd

Fourth Advisor's Committee Title

Committee Member

Keywords

biochemistry, cancer biology, cell biology, nutritional and metabolic diseases

Date of Defense

11-8-2019

Abstract

INPP4B is a dual-specificity phosphatase and a tumor suppressor in prostate and breast cancers. Progression of the prostate and breast cancers depends on the androgen receptor (AR) or estrogen receptor alpha (ERα) signaling, respectively. In this work we demonstrated that INPP4B reprograms ERα transcriptional activity in breast cancer. INPP4B maintains expression and protein levels of progesterone receptor (PR), an ERα direct target gene required for mammary gland development. Consistently we demonstrated that Inpp4b knockout severely impairs lateral branching in the mammary gland of maturing virgin females. In advanced prostate cancer, activation and transcriptional reprogramming of AR frequently coincides with the loss INPP4B. We showed that INPP4B regulates AR transcriptional activity in part through inhibiting the oncogenic signaling pathways Akt and PKC. The high-fat diet (HFD) and obesity have been linked to the development of metabolic dysfunction and the promotion of multiple cancers. In obese individuals, the insulin and fatty acid mediated signaling activate AKT and PKC pathways which are involved in metabolic disorders. Therefore, we investigated the roles of INPP4B in obese models. Males were susceptible to diet-induced obesity, exhibited significant inflammation of the adipose tissue, hepatosteatosis, and type 2 diabetes. Obese HFD Inpp4b-/- males developed high grade prostatic intraepithelial neoplasia. Similar to humans, female knockout mice were protected from insulin resistance despite extreme obesity and fibrotic hepatosteatosis. The development of steatosis in Inpp4b-/- mice was caused by increased constitutive proteolytic activation of lipogenic transcription factor SREBP1 in liver. Activated SREBP1 along with the HFD caused increased expression of PPARγ and other genes that involved in de novo lipogenesis leading to the development of non-alcoholic fatty liver disease (NAFLD). Metabolic and steroid signaling changes caused mammary gland hyperplasia in obese knockout females. In conclusion, INPP4B is a tumor suppressor that regulates steroid receptor signaling and protects mice from high-fat diet induced metabolic disorders and neoplastic changes.

Identifier

FIDC008829

Previously Published In

Zhang M, Suarez E, Vasquez JL, Nathanson L, Peterson LE, Rajapakshe K, et al. Inositol polyphosphate 4-phosphatase type II regulation of androgen receptor activity. Oncogene. 2019;38(7):1121-35

Available for download on Sunday, October 17, 2021

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