Chemotherapy resistance remains a major obstacle to durable control of breast cancer (BC), particularly to doxorubicin (DOX). Heat shock protein 90 alpha family class A member 1 (HSP90AA1) and the mitochondrial outer-membrane channel VDAC1 have been implicated in tumor survival and metabolism, yet their interplay and contribution to PI3K/AKT-driven chemoresistance in BC are incompletely defined. We examined the expression of HSP90AA1 and VDAC1 in BC tissues by immunohistochemistry, and cell lines by qRT-PCR and Western blotting. The clinical significance of their expression was analyzed in 125 BC patients. Functional studies using gene overexpression, knockdown, and DOX-resistant cell models were performed to assess proliferation, migration, invasion, and chemoresistance. The molecular mechanisms were investigated via pathway analyses and rescue experiments. In vivo xenograft models were employed to validate the effects of HSP90AA1/VDAC1 modulation and PI3K/AKT pathway inhibition on tumor growth and DOX sensitivity. HSP90AA1 and VDAC1 were significantly upregulated in BC tissues and cell lines, with high expression correlating with advanced clinicopathological features and poor prognosis. Functional assays revealed that HSP90AA1 contributed to increased proliferation, migration, invasion, and DOX resistance in BC cells, and these effects were attenuated by VDAC1 silencing, suggesting a functional link between HSP90AA1 and VDAC1. Mechanistically, dysregulated HSP90AA1/VDAC1 signaling was associated with increased activation of the PI3K/AKT pathway. This alteration was accompanied by upregulation of multidrug resistance–related proteins (ABCB1, ABCG2, and MRP2) and reduced apoptosis. Knockdown of HSP90AA1 or VDAC1, particularly in combination, restored DOX sensitivity and reduced malignant behaviors in resistant BC cells. In vivo, HSP90AA1 overexpression accelerated tumor growth, while VDAC1 silencing or PI3K/AKT inhibition significantly suppressed progression and enhanced DOX efficacy without systemic toxicity. Our findings support a model in which HSP90AA1–VDAC1–PI3K/AKT signaling contributes to BC progression and DOX resistance. Targeting this pathway, either by dual inhibition of HSP90AA1 and VDAC1 or by blocking PI3K/AKT signaling, may represent a promising therapeutic strategy to overcome chemoresistance in BC.
Fang et al. (Tue,) studied this question.