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.

蒽环类药物是一类常规常用的治疗乳腺癌的一线化疗药物。然而，基于蒽环类药物的方案只能将乳腺癌死亡率降低 20-30%。此外，目前还没有合适的生物标志物来预测对这种化疗的反应。在这里，我们报告了我们的发现，这些发现可能通过显示 AQP1（水通道蛋白 1）蛋白作为蒽环类化疗的潜在反应预测因子来填补这一空白。我们发现，与 AQP1 表达水平低的乳腺癌患者相比，接受蒽环类药物治疗的 AQP1 表达水平高的乳腺癌患者具有更好的临床结果。在探索潜在机制的过程中，我们发现 AQP1 和糖原合酶激酶 3β (GSK3β) 与 12 个犰狳重复序列竞争性相互作用，β-catenin 被抑制，导致 β-catenin 在细胞质中积累和核易位。核 β-catenin 与 TopoIIα 相互作用并增强 TopoIIα 的活性，导致乳腺癌细胞对蒽环类药物的高度敏感性。我们还发现，miR-320a-3p 可以通过抑制 AQP1 表达来减弱蒽环类药物的化学敏感性。总之，我们的研究结果表明 AQP1 作为蒽环类化疗反应预测因子的功效。我们研究的应用包括但不限于，