PDF(Pubmed)
Abstract：
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.
摘要：
AQP有助于乳腺癌的进展和转移。我们先前发现Aqp7的遗传抑制降低了乳腺癌的原发肿瘤负荷和转移。在这项研究中,我们使用了两种AQP抑制剂，Auphen和Z433927330，以评估治疗性抑制AQPs在乳腺癌治疗中的疗效。在乳腺癌中评估抑制剂在鼠和人乳腺癌细胞系中的细胞毒性和代谢稳定性测定。两种AQP抑制剂还影响其他AQP转录物和蛋白质的表达，这表明AQP家庭成员之间的补偿性调节。作为一个单一的代理人，体内Auphen治疗延长了总生存期，但不影响原发性或转移性肿瘤负荷。然而,Auphen治疗使细胞对化疗（阿霉素）或内分泌治疗（他莫昔芬，富维司坦）。事实上,用他莫昔芬治疗可降低整体AQP7蛋白表达。用Auphen治疗的乳腺癌细胞的RNA-seq鉴定了受Auphen影响的线粒体代谢基因，并可能有助于减少乳腺肿瘤的进展。肺转移,和提高内分泌治疗乳腺癌的疗效。有趣的是,我们发现Auphen和他莫昔芬合作降低乳腺癌细胞的活力，这表明Auphen治疗使细胞对他莫昔芬更敏感。一起,这项研究强调了AQPs作为乳腺癌转移的治疗弱点,是有希望的,应该加以利用.然而,药理学结果表明,需要对AQP抑制剂进行进一步的化学改进和优化,以使这些AQP抑制剂适用于克服内分泌治疗耐药的治疗获益.
