AQPs contribute to breast cancer progression and metastasis. We previously found that genetic inhibition of Aqp7 reduces primary tumor burden and metastasis in breast cancer. In this study, we utilized two AQP inhibitors, Auphen and Z433927330, to evaluate the efficacy of therapeutic inhibition of AQPs in breast cancer treatment. The inhibitors were evaluated in breast cancer for both cytotoxicity and metabolic stability assays across both murine and human breast cancer cell lines. Both AQP inhibitors also affected the expression of other AQP transcripts and proteins, which demonstrates compensatory regulation between AQP family members. As a single agent, Auphen treatment in vivo extended overall survival but did not impact primary or metastatic tumor burden. However, Auphen treatment made cells more responsive to chemotherapy (doxorubicin) or endocrine treatment (tamoxifen, fulvestrant). In fact, treatment with Tamoxifen reduced overall AQP7 protein expression. RNA-seq of breast cancer cells treated with Auphen identified mitochondrial metabolism genes as impacted by Auphen and may contribute to reducing mammary tumor progression, lung metastasis, and increased therapeutic efficacy of endocrine therapy in breast cancer. Interestingly, we found that Auphen and tamoxifen cooperate to reduce breast cancer cell viability, which suggests that Auphen treatment makes the cells more susceptible to Tamoxifen. Together, this study highlights AQPs as therapeutic vulnerabilities of breast cancer metastasis that are promising and should be exploited. However, the pharmacologic results suggest additional chemical refinements and optimization of AQP inhibition are needed to make these AQP inhibitors appropriate to use for therapeutic benefit in overcoming endocrine therapy resistance.
水通道蛋白（AQPs）在乳腺癌进展和转移过程中发挥重要作用。我们先前研究发现，通过基因手段抑制Aqp7能够降低乳腺癌的原发肿瘤负荷和转移率。本研究采用两种AQP抑制剂（Auphen和Z433927330），评估了治疗性抑制AQPs在乳腺癌治疗中的效果。我们在小鼠和人类乳腺癌细胞系中，对这两种抑制剂进行了细胞毒性和代谢稳定性检测。两种AQP抑制剂均能影响其他AQP转录本和蛋白的表达，这表明AQP家族成员之间存在代偿性调节机制。作为单一用药，Auphen在体内治疗能延长总生存期，但对原发或转移性肿瘤负荷无显著影响。然而，Auphen处理使肿瘤细胞对化疗药物（多柔比星）或内分泌治疗药物（他莫昔芬、氟维司群）更为敏感。事实上，他莫昔芬治疗能降低整体AQP7蛋白表达水平。对经Auphen处理的乳腺癌细胞进行RNA测序分析发现，线粒体代谢相关基因受到Auphen影响，这可能有助于减缓乳腺肿瘤进展、减少肺转移，并增强乳腺癌内分泌治疗的疗效。值得注意的是，我们发现Auphen与他莫昔芬具有协同降低乳腺癌细胞存活率的作用，这表明Auphen处理使细胞对他莫昔芬更为敏感。综上所述，本研究揭示AQPs可作为乳腺癌转移的治疗靶点，具有良好应用前景且值得深入开发。然而，药理学结果表明，需要进一步优化AQP抑制剂的化学结构并改进抑制策略，才能使这些AQP抑制剂适用于克服内分泌治疗耐药性，从而获得临床治疗效益。
Evaluation of the Mammalian Aquaporin Inhibitors Auphen and Z433927330 in Treating Breast Cancer
肿瘤(癌症)患者之家