TMEM97/SIGMA 2 RECEPTOR INCREASES ESTROGEN RECEPTOR ΑLPHA ACTIVITY TO PROMOTE BREAST CANCER PROLIFERATION

Author

Yuanqin Zhang, Southern Illinois University CarbondaleFollow

Date of Award

6-1-2021

Degree Name

Doctor of Philosophy

Department

Molecular Biology, Microbiology and Biochemistry

First Advisor

Nie, Daotai

Abstract

Breast cancer is the most common cancer in women among nearly every racial and ethnic group. About one in eight women in the US will get breast cancer in her lifetime. Sigma 2 receptor has long been implicated in breast carcinogenesis and compounds binding to this receptor have been developed as imaging agents for breast cancer, but its molecular identity had been elusive until 2017 when TMEM97 was identified as sigma 2 receptor. It is highly important to determine whether the biological functions of TMEM97 protein defined in previous studies are overlapping with those linked to sigma 2 receptor. In this study, we found that TMEM97 is highly expressed in ER positive breast tumors and its expression levels are associated with poor overall survival rate of breast cancer patients, and its expression patten is strongly correlated with ER and PR but not with HER2 status. Breast cancer cells with TMEM97 overexpression showed growth advantage over the control cells both in nutrition sufficient and starvation conditions. The differences were more pronounced under estrogen depleted conditions. In breast cancer MCF7 and T47D cells, TMEM97/sigma 2 receptor could regulate ERα transcriptional activities, and also regulate mTOR/S6K1 signaling pathways. The increased level of active, phosphorylated ERα, and the increased resistance to Tamoxifen treatment could be blocked by a mTOR inhibitor. TMEM97 in ER positive breast cancer cells could retard and delay the estradiol caused ERα turnover because of the accelerated the ERα protein synthesis offsetting the degradation caused by estradiol. TMEM97 increases the transactivated ERα, specifically for the nuclear soluble and chromatin bounded ERα. These observations suggest that TMEM97/sigma 2 receptor participates in breast tumor cell growth driven by estrogen signaling and further regulates the transcriptional activities of ERα through modulating ERα binding to estradiol and subsequent nuclear localization. Further, increased TMEM97 expression renders breast cancer cells with increased resistance toward endocrine therapeutics such as tamoxifen, which make TMEM97 a valid target of intervention to modulate ER activities to reduce resistance toward endocrine therapy.