TMEM97 Drives Estrogen Receptor Activation and Tamoxifen Resistance via mTOR/S6K1 Signaling in Breast Cancer

Breast cancer is the most common cancer diagnosed in women, accounting for more than 1 in 10 new cancer diagnosis annually and is the second most common cause of cancer death among women worldwide. Estrogen receptor alpha (ERα) signaling plays a central role in the growth and progression of the majority of breast tumors types. Because of this, oncologists commonly use selective estrogen receptor modulators like tamoxifen to treat these patients. However, one of the major challenges in managing ER-positive breast cancer is the frequent emergence of resistance to these therapies, either from the outset or during treatment which diminishes the effectiveness of tamoxifen and can lead to treatment failures and further progression of the cancer. Despite advancements in endocrine therapy, the underlying molecular mechanisms that cause this resistance remain poorly understood and urgently need to be clarified.

TMEM97 also known as the Sigma-2 receptor has recently emerged as a potential factor in breast cancer progression and therapy resistance, but its specific role in modulating ERα activity and contributing to tamoxifen resistance was not well understood.  To address this gap and determine whether TMEM97 could be a viable therapeutic target, recent study published in the Cancers Journal and conducted by Dr. Yuanqin Zhang (currently Postdoctoral Fellow at Washington University in St Louis), Xiangwei Fang, Jiuhui Wang, and led by Professor Daotai Nie from the Southern Illinois University School of Medicine -Simmons Cancer Institute, the researchers investigated TMEM97 interactions with ERα and its influence on key signaling pathways, such as mTOR/S6K1, and uncovered mechanisms that might help overcome resistance and improve the efficacy of treatments for ER-positive breast cancer

To achieve this, the research team performed a series of experiments on two ER-positive breast cancer cell lines, MCF7 and T47D. They used lentiviral vectors to either overexpress or knock down TMEM97 and evaluated how these manipulations influenced cell proliferation and tamoxifen resistance. They found that overexpressing TMEM97 significantly enhanced the growth of breast cancer cells under both estrogen-rich and estrogen-deprived conditions which indicated that TMEM97 promotes cell proliferation. In contrast, TMEM97 knock-down reduced the growth of these cells which highlights its importance in supporting breast cancer cell survival. Moreover, the authors used luciferase reporter assays to show that TMEM97 overexpression increased ERα transcriptional activity even in the absence of estrogen which demonstrated that TMEM97 can activate ERα independently. These results were further corroborated by the overexpression of estrogen-responsive genes like NRIP1 and ABCA3. On the other hand, knocking down TMEM97 reduced ERα activity and downregulated these target genes, confirming TMEM97 role in driving ERα signaling. Furthermore, the researchers also investigated how TMEM97 contributes to tamoxifen resistance, a major issue in treating ER-positive breast cancer. They treated TMEM97-overexpressing cells with tamoxifen and found that these cells were much more resistant to the drug with higher survival rates than the control cells. According to the authors, this tamoxifen resistance appeared to be linked to increased phosphorylation of ERα at serine 167 (S167), a modification known to promote resistance. In contrast, this phosphorylation was absent in TMEM97-knockdown cells, which suggest to the authors that reducing TMEM97 could enhance tamoxifen sensitivity. To better understand the mechanisms behind TMEM97’s role in tamoxifen resistance, the researchers explored its involvement in the mTOR/S6K1 signaling pathway which is known to be implicated in ERα regulation and found that overexpression of TMEM97 activated this pathway leading to increased ERα phosphorylation at S167. When the authors treated the cells with the mTOR inhibitor rapamycin, it reduced both ERα phosphorylation and tamoxifen resistance which means that TMEM97-mediated resistance operates through mTOR/S6K1 signaling. In contrast, knocking down TMEM97 inhibited this pathway and decreased tamoxifen resistance, further highlighting its importance in therapy resistance.

In conclusion, Dr.  Zhang and Professor Daotai Nie identified TMEM97 as a key regulator of ERα activity and a major contributor to tamoxifen resistance. These findings provide valuable data into how TMEM97 drives tumor growth and survival even in the absence of estrogen, and highlights its role in activating the mTOR/S6K1 pathway. Indeed, targeting TMEM97 or the mTOR/S6K1 pathway could lead to new therapeutic strategies that restore sensitivity to tamoxifen treatments and improve outcomes for patients. Indeed, the development of TMEM97 inhibitors could represent a new class of targeted therapies for managing resistant breast cancer. Moreover, the study suggests that TMEM97 could serve as a diagnostic biomarker for stratifying patients at risk of developing resistance to tamoxifen and other endocrine therapies. Additionally, the research also opens up the possibility of combining tamoxifen with mTOR inhibitors like rapamycin as a potentially effective approach for patients with high TMEM97 expression.