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Background and objective <p>Triple-negative breast cancer (TNBC) is an aggressive subtype characterized by the absence of estrogen receptor, progesterone receptor, and HER2 overexpression. Its poor prognosis arises from a combination of factors, including the lack of targeted therapeutic options, intrinsic tumor aggressiveness, and high recurrence and metastasis rates. Chemotherapy remains the mainstay of treatment; however, drug resistance poses a major clinical challenge. Emerging evidence suggests that Transient Receptor Potential (TRP) channels, key regulators of calcium signaling and cellular stress responses, may contribute to tumor progression and influence sensitivity to anticancer drugs. Therefore, this study aimed to investigate the role of TRP channels in mediating chemotherapy resistance in TNBC.</p> Methods <p>TNBC cell lines (MDA-MB-231, SUM-159PT, and BT-20), Luminal A breast cancer cell lines (MCF-7 and T-47D) and HER2 + breast cancer cell line (SkBr3) were exposed to a chemotherapy regimen consisting of epirubicin, cyclophosphamide, and paclitaxel (ECP) to model treatment conditions. TRP channel expression was quantified by real-time PCR. The functional role of TRPM2 was investigated through siRNA-mediated silencing and pharmacological inhibition using tatM2NX. Cell viability, apoptosis, mitochondrial calcium dynamics, and oxidative stress were assessed using established biochemical and imaging-based assays. In addition, the functional relationship between miR-6791 and TRPM2 was explored through miRNA overexpression experiments, with subsequent evaluation of TRPM2 expression and the effects on cell viability.</p> Results <p>TRPM2 expression was strongly induced in TNBC cells following ECP treatment compared with untreated controls. This upregulation promoted cell survival and limited apoptosis under chemotherapy stress, in part by supporting mitochondrial function and calcium homeostasis. In contrast, TRPM2 inhibition using siRNA or the peptide inhibitor tatM2NX sensitized TNBC cells to ECP, increased apoptotic cell death, and disrupted mitochondrial calcium balance. In addition, miR-6791 emerged as a negative regulator of TRPM2, and its overexpression reduced TRPM2 levels and partially restored chemosensitivity in resistant TNBC cells.</p> Conclusions <p>TRPM2 acts as a critical mediator of chemotherapy resistance in TNBC. Targeting TRPM2 directly or through its upstream regulator miR-6791 may represent a promising strategy to enhance chemosensitivity and improve clinical outcomes in TNBC patients.</p>

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TRPM2 channel increases cell viability of triple negative breast cancer cells following chemotherapy through altered mitochondrial calcium homeostasis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月29日

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  • Mayar Soussi,
  • Alice Hasselsweiller,
  • Dmitri Gordienko,
  • Evan Courmont,
  • Ayşenur Nazıroğlu,
  • Mustafa Nazıroğlu,
  • Joséphine Louvieaux,
  • Loïc Lemonnier,
  • Chann Lagadec,
  • Xuefen Le Bourhis,
  • Anna Rita Cantelmo,
  • Dimitra Gkika

摘要

Background and objective

Triple-negative breast cancer (TNBC) is an aggressive subtype characterized by the absence of estrogen receptor, progesterone receptor, and HER2 overexpression. Its poor prognosis arises from a combination of factors, including the lack of targeted therapeutic options, intrinsic tumor aggressiveness, and high recurrence and metastasis rates. Chemotherapy remains the mainstay of treatment; however, drug resistance poses a major clinical challenge. Emerging evidence suggests that Transient Receptor Potential (TRP) channels, key regulators of calcium signaling and cellular stress responses, may contribute to tumor progression and influence sensitivity to anticancer drugs. Therefore, this study aimed to investigate the role of TRP channels in mediating chemotherapy resistance in TNBC.

Methods

TNBC cell lines (MDA-MB-231, SUM-159PT, and BT-20), Luminal A breast cancer cell lines (MCF-7 and T-47D) and HER2 + breast cancer cell line (SkBr3) were exposed to a chemotherapy regimen consisting of epirubicin, cyclophosphamide, and paclitaxel (ECP) to model treatment conditions. TRP channel expression was quantified by real-time PCR. The functional role of TRPM2 was investigated through siRNA-mediated silencing and pharmacological inhibition using tatM2NX. Cell viability, apoptosis, mitochondrial calcium dynamics, and oxidative stress were assessed using established biochemical and imaging-based assays. In addition, the functional relationship between miR-6791 and TRPM2 was explored through miRNA overexpression experiments, with subsequent evaluation of TRPM2 expression and the effects on cell viability.

Results

TRPM2 expression was strongly induced in TNBC cells following ECP treatment compared with untreated controls. This upregulation promoted cell survival and limited apoptosis under chemotherapy stress, in part by supporting mitochondrial function and calcium homeostasis. In contrast, TRPM2 inhibition using siRNA or the peptide inhibitor tatM2NX sensitized TNBC cells to ECP, increased apoptotic cell death, and disrupted mitochondrial calcium balance. In addition, miR-6791 emerged as a negative regulator of TRPM2, and its overexpression reduced TRPM2 levels and partially restored chemosensitivity in resistant TNBC cells.

Conclusions

TRPM2 acts as a critical mediator of chemotherapy resistance in TNBC. Targeting TRPM2 directly or through its upstream regulator miR-6791 may represent a promising strategy to enhance chemosensitivity and improve clinical outcomes in TNBC patients.