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

Area of Science:

• Oncology
• Molecular Biology
• Endocrinology

Background:

• Aberrant estrogen receptor (ER) signaling drives breast tumor growth.
• The molecular identity of the sigma 2 receptor, implicated in breast carcinogenesis, was elusive until TMEM97 was identified.
• TMEM97/sigma 2 receptor expression is linked to ER-positive breast tumors.

Purpose of the Study:

• To investigate the role of TMEM97/sigma 2 receptor in ER-positive breast cancer.
• To determine the correlation between TMEM97 expression and clinical parameters.
• To elucidate the molecular mechanisms by which TMEM97 influences breast cancer cell growth and treatment response.

Main Methods:

• Analysis of TMEM97 expression in breast tumors and correlation with ER, PR, and HER2 status.
• Assessment of TMEM97's effect on breast cancer cell proliferation and survival under various conditions.
• Investigation of TMEM97's impact on ERα transcriptional activity, mTOR/S6K1 signaling, and tamoxifen sensitivity.
• Utilizing gene knockdown and pharmacological inhibition (mTOR inhibitor).

Main Results:

• TMEM97 is highly expressed in ER-positive breast tumors, correlating with ER/PR status and reduced patient survival.
• Increased TMEM97 expression enhances breast cancer cell growth, promotes resistance to tamoxifen, and supports growth under estrogen-depleted conditions.
• TMEM97 upregulates ERα transcriptional activity and stimulates mTOR/S6K1 signaling pathways.
• mTOR inhibition blocks TMEM97-induced ERα activation and tamoxifen resistance; TMEM97 knockdown sensitizes cells to tamoxifen.

Conclusions:

• TMEM97/sigma 2 receptor is a novel regulator of ERα activity in breast tumor cells.
• TMEM97 expression is a significant prognostic marker in ER-positive breast cancer.
• Targeting TMEM97 or its downstream signaling pathways (mTOR) may represent a therapeutic strategy for overcoming tamoxifen resistance in breast cancer.