Zhang, Y.; Fang, X.; Wang, J.; Nie, D. TMEM97/Sigma 2 Receptor Increases Estrogen Receptor α Activity in Promoting Breast Cancer Cell Growth. Cancers2023, 15, 5691.
Zhang, Y.; Fang, X.; Wang, J.; Nie, D. TMEM97/Sigma 2 Receptor Increases Estrogen Receptor α Activity in Promoting Breast Cancer Cell Growth. Cancers 2023, 15, 5691.
Zhang, Y.; Fang, X.; Wang, J.; Nie, D. TMEM97/Sigma 2 Receptor Increases Estrogen Receptor α Activity in Promoting Breast Cancer Cell Growth. Cancers2023, 15, 5691.
Zhang, Y.; Fang, X.; Wang, J.; Nie, D. TMEM97/Sigma 2 Receptor Increases Estrogen Receptor α Activity in Promoting Breast Cancer Cell Growth. Cancers 2023, 15, 5691.
Abstract
Aberrant estrogen receptor (ER) signaling is a major driver of breast tumor growth and progression. Sigma 2 receptor has long been implicated in breast carcinogenesis based on pharmacological studies, but its molecular identity had been elusive until TMEM97 was identified as the receptor. Herein we report that TMEM97/sigma 2 receptor is highly expressed in ER positive breast tumors and its expression is strongly correlated with ER and progesterone receptor (PR) but not with HER2 status. High expression levels of TMEM97 are associated with reduced overall survival of patients. Breast cancer cells with increased expression of TMEM97 had growth advantage over the control cells under both nutrition limiting and sufficient conditions, while knockdown of TMEM97 expression reduced tumor cell proliferations. When compared to their vector control cells, MCF7 and T47D cells with increased TMEM97 expression presented increased resistance to tamoxifen treatment and also grew better under estrogen depleted conditions. TMEM97/sigma 2 receptor enhanced ERα transcriptional activities and increased the level of transactivated ERα, especially the nuclear soluble and chromatin bounded ERα. Increased TMEM97 also stimulated mTOR/S6K1 signaling pathways in MCF7 and T47D cells. The increased level of active, phosphorylated ERα, and the enhanced resistance to tamoxifen treatment with increased TMEM97 could be blocked by an mTOR inhibitor. Knockdown of TMEM97 expression reduced ERα and mTOR/S6K1 signaling activities, rendering the cells with increased sensitivity to tamoxifen. The observations suggest that TMEM97/sigma 2 receptor is a novel regulator of ERα activities in breast tumor cell growth.
Medicine and Pharmacology, Oncology and Oncogenics
Copyright:
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
