2. Academic Validation
  3. ATP6V0D2 drives triple-negative breast cancer progression and inhibits cisplatin sensitivity by promoting PHLPP2 lysosomal degradation

ATP6V0D2 drives triple-negative breast cancer progression and inhibits cisplatin sensitivity by promoting PHLPP2 lysosomal degradation

  • iScience. 2025 Oct 27;28(11):113853. doi: 10.1016/j.isci.2025.113853.
Jingyu Zhang 1 2,  Congbo Cao 1,  Hongyu Yang 3,  Liu Yang 1,  Meiqi Wang 1,  Xiaohan Liu 1,  Xin Hao 1,  Yuanyuan Zhang 3,  Xiaohan Wang 1 4 5,  Zhenchuan Song 1 5
Affiliations

Affiliations

  • 1 Department of Breast Disease Center, the Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, China.
  • 2 Breast Center, Peking University People's Hospital, Beijing 100044, China.
  • 3 State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
  • 4 Postdoctoral Research Station at The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, China.
  • 5 Key Laboratory for Breast Cancer Molecular Medicine of Hebei Province, Shijiazhuang, Hebei 050011, China.
PMID: 41312388 DOI: 10.1016/j.isci.2025.113853
Abstract

Triple-negative breast Cancer (TNBC) faces therapeutic challenges due to limited treatment options and frequent chemoresistance. In this study, we identify ATP6V0D2 as a key factor upregulated in TNBC, where its expression correlates with poor prognosis. Transcriptomic and functional analyses linked ATP6V0D2 to PI3K/Akt signaling and platinum drug resistance. Mechanistically, ATP6V0D2 enhanced lysosomal function to promote degradation of the tumor suppressor PHLPP2, thereby sustaining Akt phosphorylation. Functional assays showed that ATP6V0D2 knockdown increased cisplatin sensitivity both in vitro and in vivo. Furthermore, pharmacological inhibition of V-ATPase with bafilomycinA1 sensitized TNBC patient-derived organoids to cisplatin. Clinically, our analysis of 91 TNBC patients who received cisplatin-based neoadjuvant chemotherapy found that high ATP6V0D2 expression was inversely correlated with pathological complete response (pCR), whereas PHLPP2 levels showed positive association, supporting the proposed mechanistic link. Together, these findings highlight the impact of ATP6V0D2 on TNBC progression and cisplatin sensitivity, nominating ATP6V0D2 as a promising therapeutic target.

Keywords

Cancer; Target identification; Therapeutics.

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