文章：

TMEM97/σ2受体通过增强雌激素受体α活性促进乳腺癌细胞生长

TMEM97/Sigma 2 Receptor Increases Estrogen Receptor α Activity in Promoting Breast Cancer Cell Growth

原文发布日期：2 December 2023

DOI: 10.3390/cancers15235691

类型: Article

开放获取: 是

英文摘要：

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 the TMEM97/sigma 2 receptor is highly expressed in ER-positive breast tumors and its expression is strongly correlated with ERs and progesterone receptors (PRs) 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 a growth advantage over the control cells under both nutrition-limiting and sufficient conditions, while the 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. The TMEM97/sigma 2 receptor enhanced the ERα transcriptional activities and increased the expression of genes responsive to estrogen treatment. Increased TMEM97 also stimulated the mTOR/S6K1 signaling pathways in the 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. The knockdown of TMEM97 expression reduced the ERα and mTOR/S6K1 signaling activities, rendering the cells with an increased sensitivity to tamoxifen. The observations suggest that the TMEM97/sigma 2 receptor is a novel regulator of ERα activities in breast tumor cell growth.

摘要翻译： 

雌激素受体（ER）信号通路异常是驱动乳腺肿瘤生长与进展的主要因素。基于药理学研究，Sigma 2受体长期以来被认为与乳腺癌发生相关，但其分子身份一直未能明确，直至TMEM97被确认为该受体。本文研究发现，TMEM97/sigma 2受体在ER阳性乳腺肿瘤中高表达，其表达水平与ER及孕激素受体（PR）呈显著正相关，而与HER2状态无关。TMEM97高表达与患者总生存期缩短相关。在营养受限及充足条件下，TMEM97表达升高的乳腺癌细胞相较于对照细胞均表现出生长优势，而敲低TMEM97表达则抑制肿瘤细胞增殖。与载体对照组相比，TMEM97表达升高的MCF7和T47D细胞对他莫昔芬治疗产生更强耐药性，且在雌激素剥夺条件下生长更佳。TMEM97/sigma 2受体能增强ERα转录活性，并提升雌激素应答基因的表达水平。TMEM97表达升高还可激活MCF7和T47D细胞中的mTOR/S6K1信号通路。TMEM97升高导致的ERα磷酸化激活水平增强及他莫昔芬耐药性增加，均可被mTOR抑制剂阻断。敲低TMEM97表达可降低ERα及mTOR/S6K1信号活性，使细胞对他莫昔芬的敏感性增强。这些发现表明，TMEM97/sigma 2受体是乳腺肿瘤细胞生长过程中ERα活性的新型调控因子。

原文链接：

TMEM97/Sigma 2 Receptor Increases Estrogen Receptor α Activity in Promoting Breast Cancer Cell Growth