The Effect of Aquaporin-7 on Breast Cancer Progression and Therapeutic Resistance

The complex yet interrelated connections between cancer metabolism, gene expression, and oncogenic driver genes have the potential to identify novel biomarkers and drug targets with prognostic and therapeutic value. We effectively integrated metabolomics and gene expression data from breast cancer mouse models through a novel unbiased correlation-based network analysis. This approach identified 35 metabolite and 34 gene hubs with the most network correlations. These hubs have prognostic value and are likely integral to tumor metabolism and breast cancer. We focused on the gene hub Aquaporin-7 (human AQP7/mouse Aqp7), a water and glycerol channel, as a novel regulator of breast cancer. We identified AQP7 as a negative prognostic marker of overall survival and metastasis in breast cancer patients. Both in vitro and in vivo experiments showed that AQP7 is required for proliferation, primary tumor progression, and metastasis. Metabolomics on Aqp7 knockdown cells and tumors revealed significantly altered lipid levels, redox, and urea/arginine metabolism. Given the correlation of AQP7 with breast cancer and its involvement in glycerol transport and lipid homeostasis, we investigated AQP7 as a metabolic target for cancer therapy.

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. Our data support AQP7 expression being higher in tumors from breast cancer patients that do not respond to endocrine therapy compared to those that do respond. We investigated whether AQP7 inhibition can increase the therapeutic efficacy of endocrine therapy in breast cancer. Interestingly, we see therapeutic synergy between the aquaporin inhibitor Auphen and endocrine therapy tamoxifen, which suggests that Auphen treatment makes the cells more susceptible to tamoxifen. Aqp7 is a novel therapeutic target that provides a metabolic vulnerability in breast cancer and can be targeted to inhibit breast cancer metastasis in combination with endocrine therapy. Together, this study highlights AQP7 as a potential cancer-specific therapeutic vulnerability, and AQP7 inhibition can be exploited for therapeutic benefit in overcoming endocrine therapy resistance.

We find that Aqp7 regulates the lower TCA cycle and does not play a key role in the flux of metabolites through glycolysis. Increased expression of hAQP7/mAqp7 significantly alter gene expression, particularly in genes involved in cell proliferation, migration, and response to DNA damage. Structure-function analysis of conserved structural features of Aqp7 plays a role in maintaining metabolic homeostasis. Additionally, these structural features may contribute to additional cancer phenotypes like proliferation and adhesion. Together, this study provides new insight into how AQP7 alters metabolism and AQP7 structure-function relationships, which will provide information that can be used to develop metabolism-targeting therapies and AQP associated drugs for clinical anticancer therapy.