Aquaporin 1 promotes sensitivity of anthracycline chemotherapy in breast cancer by inhibiting β-catenin degradation to enhance TopoIIα activity

Abstract

Anthracyclines are a class of conventional and commonly used frontline chemotherapy drugs to treat breast cancer. However, the anthracycline-based regimens can only reduce breast cancer mortality by 20–30%. Furthermore, there is no appropriate biomarker for predicting responses to this kind of chemotherapy currently. Here we report our findings that may fill this gap by showing the AQP1 (Aquaporin1) protein as a potential response predictor in the anthracycline chemotherapy. We showed that breast cancer patients with a high level of AQP1 expression who underwent the anthracycline treatment had a better clinical outcome relative to those with a low level of AQP1 expression. In the exploration of the underlying mechanisms, we found that the AQP1 and glycogen synthase kinase-3β (GSK3β) competitively interacted with the 12 armadillo repeats of β-catenin, followed by the inhibition of the β-catenin degradation that led to β-catenin’s accumulation in the cytoplasm and nuclear translocation. The nuclear β-catenin interacted with TopoIIα and enhanced TopoIIα’s activity, which resulted in a high sensitivity of breast cancer cells to anthracyclines. We also found, the miR-320a-3p can attenuate the anthracycline’s chemosensitivity by inhibiting the AQP1 expression. Taken together, our findings suggest the efficacy of AQP1 as a response predictor in the anthracycline chemotherapy. The application of our study includes, but is not limited to, facilitating screening of the most appropriate breast cancer patients (who have a high AQP1 expression) for better anthracycline chemotherapy and improved prognosis purposes.

Inhibition of aquaporins as a potential adjunct to breast cancer cryotherapy

“…Previous studies have demonstrated AQP1 to be upregulated in breast cancer cells and this has been associated with enhanced cell proliferation and invasion, which may make AQP1 a potential prognostic marker for breast cancer (38,66). The increase of AQP1 in MDA-MB-231 following freezing that was observed in the present study may promote the cell's tolerance to cryo-damage as the knockdown of AQP1 expression decreased MDA-MB-231 cell viability.…”

MicroRNA 320, an Anti-Oncogene Target miRNA for Cancer Therapy

“…The downregulation of miR-320 has been reported to be relevant to drug resistance to treatments such as oxaliplatin, epirubicin, gemcitabine, tamoxifen, and doxorubicin [ 34 , 77 , 85 , 86 , 87 , 88 , 89 ]. However, the drug resistance mechanisms utilized in these examples are not fully understood.…”

“…For example, Wan et al [ 34 , 63 ] reported that overexpression of miR-320 could elevate the sensitivity of CRC cells to 5-Fu and oxaliplatin by targeting forkhead box M1 (FOXM1) . Chong et al reported that upregulation of hsa-miR-320a-3p decreased the sensitivity of primary BC cells to epirubicin [ 85 ]. Moreover, the expression of hsa-miR-320a-3p was significantly negatively associated with anthracycline sensitivity.…”

Aquaporin‐1 in breast cancer

“…Moreover, overexpression of AQP1 in the MDA-MB-231 breast cancer cells inhibited the degradation of b-catenin, which was attributed to the Cterminal tail of AQP1 interacting with 12 armadillo repeats of b-catenin [65]. Subsequently, b-catenin translocated into the nucleus where it interacted with Topoisomerase II alpha (TopoIIa), thereby enhancing sensitivity to the chemotherapeutic drug Epirubicin, used in treatment of breast cancer [65].…”