Aquaporin 5 and Nuclear Factor Erythroid 2-Related Factor 2 Upregulation in Tumor and Stroma Is Associated with Poor Pathological Complete Response to Neoadjuvant Chemotherapy in Breast Cancer.

Abstract

Objective: Breast cancer remains a leading cause of global mortality in women, with therapy resistance posing a major challenge to successful treatment. Chemotherapy-induced oxidative stress can trigger adaptive survival mechanisms through the antioxidative transcription factor NRF2 and membrane pores known as peroxiporins. Peroxiporins regulate cellular redox homeostasis by controlling the flux of H₂O₂, potentially driving the development of chemoresistance in aggressive subtypes. This study investigated the expression of peroxiporins, AQP3 and AQP5, and the antioxidative transcription factor NRF2, before and after chemotherapy to determine their role in chemotherapy resistance in HER2-positive and triple-negative breast cancer.

Subjects and methods: In this retrospective study, we analyzed the expressions of AQP3, AQP5, and NRF2 by immunohistochemical staining in paired clinical biopsy samples of HER2-positive (N = 75) and triple-negative (N = 56) breast cancer patients. We evaluated target protein expression across both tumor and surrounding stroma within these tissue samples.

Results: Chemotherapy significantly increased AQP5 and NRF2 expression in both tumor cells and stroma across both subtypes. However, when stratified by therapy response, significant upregulation of AQP5 and nuclear NRF2 was observed only in the pathological incomplete response group. In contrast, patients achieving a complete response showed no significant changes in protein expression post-therapy.

Conclusion: Chemotherapy is associated with increased AQP5 expression and NRF2 nuclear translocation within both tumor cells and stroma. These post-therapy molecular changes are significantly associated with a lack of pathological complete response, suggesting that AQP5 and NRF2 may be involved in resistance to chemotherapy in HER2-positive and TNBC.

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