Abstract 1525: Regulation of cellular metabolic stress by aquaporin-7 in breast cancer

Abstract The reprogramming of metabolism during cancer progression supports metastasis and response to therapies. The underlying relationships between cancer metabolism, gene expression, and oncogenic driver genes have the potential to identify novel biomarkers and targets with prognostic and therapeutic value. To understand these relationships, we used a novel unbiased correlation-based network analysis to integrate metabolomics and gene expression data from breast cancer mouse models to identify driver genes and metabolic pathways of mammary cancer. This approach identified 35 metabolite and 34 gene hubs with the most network correlations. Significantly, these hubs have prognostic value and likely are integral to tumor metabolism and breast cancer. The gene hub Aquaporin-7 (human AQP7/mouse Aqp7), a water and glycerol channel, emerged as a novel regulator of breast cancer. We identified AQP7 as a negative prognostic marker of overall survival and metastasis in breast cancer patients. In vitro and in vivo experiments showed that AQP7 is required for proliferation, primary tumor progression, and lung metastasis. Metabolomics of Aqp7 knockdown mammary cancer cells and tumors further revealed significantly altered lipid levels, redox, and urea/arginine metabolism. Given the prognostic value of AQP7 with breast cancer and its involvement in glycerol transport and lipid homeostasis, we investigated the metabolic reprogramming by AQP7 and evaluated the efficacy of AQP7 inhibition as a cancer therapeutic. We find that AQP7 is a critical regulator of metabolic and signaling responses to environmental cellular stresses and of endocrine therapy efficacy in breast cancer metastasis to lung. Interestingly, in patient data, AQP7 expression is expressed higher in breast tumors that do not respond to endocrine therapy compared to tumors that do respond, which suggests that Aqp7 may be a therapeutic vulnerability in endocrine therapy resistance. We evaluated AQP7 inhibition in combination with endocrine therapy in breast cancer. Interestingly, the aquaporin inhibitor Auphen cooperated with endocrine therapy tamoxifen to reduce the viability of breast cancer cells. This suggests that Auphen treatment makes the cells more susceptible to tamoxifen. Together, this study highlights AQP7 as a potential cancer-specific therapeutic vulnerability and that AQP7 inhibition can be exploited for therapeutic benefit in overcoming endocrine therapy resistance. Citation Format: Verodia Charlestin, Chen Dai, Daniel Fulkerson, Carlos E. Arias Matus, Madeline Sheely, Man Wang, Junmin Wu, Zixuan Song, Norman J. Dovichi, Jun Li, Laurie E. Littlepage. Regulation of cellular metabolic stress by aquaporin-7 in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1525.