PDF(Pubmed)
Abstract：
OBJECTIVE: Breast cancer (BC) accounts for roughly 30% of new cancers diagnosed in women each year; thus, this cancer type represents a substantial burden for people and health care systems. Despite the existence of effective therapies to treat BC, drug resistance remains a problem and is a major cause of treatment failure. Therefore, new drugs and treatment regimens are urgently required to overcome resistance. Recent research indicates that inhibition of the endosomal recycling pathway, an intracellular membrane trafficking pathway that returns endocytosed proteins back to the plasma membrane, may be a promising strategy to downregulate clinically relevant cell surface proteins such as HER2 and HER3, and to overcome drug resistance.
METHODS: To investigate the molecular mechanism of action of an endosomal recycling inhibitor (ERI) called primaquine, we performed a reverse-phase protein array (RPPA) assay using a HER2-positive breast cancer cell line. The RPPA findings were confirmed by Western blot and RT-qPCR in several BC cell lines. Novel drug combinations were tested by MTT cell viability and clonogenic assays.
RESULTS: Among the signalling molecules downregulated by ERIs were estrogen receptor-alpha (ER-α) and androgen receptor. We confirmed this finding in other breast cancer cell lines and show that downregulation occurs at the transcriptional level. We also found that ERIs synergise with tamoxifen, a standard-of-care therapy for breast cancer.
CONCLUSIONS: Our data suggest that combining ERIs with hormone receptor antagonists may enhance their efficacy and reduce the emergence of drug resistance.
METHODS: To investigate the molecular mechanism of action of an endosomal recycling inhibitor (ERI) called primaquine, we performed a reverse-phase protein array (RPPA) assay using a HER2-positive breast cancer cell line. The RPPA findings were confirmed by Western blot and RT-qPCR in several BC cell lines. Novel drug combinations were tested by MTT cell viability and clonogenic assays.
RESULTS: Among the signalling molecules downregulated by ERIs were estrogen receptor-alpha (ER-α) and androgen receptor. We confirmed this finding in other breast cancer cell lines and show that downregulation occurs at the transcriptional level. We also found that ERIs synergise with tamoxifen, a standard-of-care therapy for breast cancer.
CONCLUSIONS: Our data suggest that combining ERIs with hormone receptor antagonists may enhance their efficacy and reduce the emergence of drug resistance.
摘要：
目的：乳腺癌（BC）每年约占女性新诊断癌症的30％；因此，这种类型的癌症对人们和医疗保健系统来说是一个巨大的负担。尽管存在治疗BC的有效疗法，耐药性仍然是一个问题，是治疗失败的主要原因。因此,迫切需要新的药物和治疗方案来克服耐药性。最近的研究表明，抑制内体再循环途径，细胞内膜运输途径，将被胞吞的蛋白质返回质膜，可能是下调HER2和HER3等临床相关细胞表面蛋白并克服耐药性的有希望的策略。
方法：为了研究称为伯氨喹的内体再循环抑制剂（ERI）的分子机制，我们使用HER2阳性乳腺癌细胞系进行了反相蛋白阵列(RPPA)检测.通过Western印迹和RT-qPCR在几种BC细胞系中证实了RPPA的发现。通过MTT细胞活力和克隆形成测定来测试新的药物组合。
结果：被ERIs下调的信号分子是雌激素受体α（ER-α）和雄激素受体。我们在其他乳腺癌细胞系中证实了这一发现，并表明下调发生在转录水平。我们还发现ERI与他莫昔芬协同作用，乳腺癌的标准治疗方法。
结论：我们的数据表明，将ERIs与激素受体拮抗剂联合使用可以增强其疗效并减少耐药性的出现。
方法：为了研究称为伯氨喹的内体再循环抑制剂（ERI）的分子机制，我们使用HER2阳性乳腺癌细胞系进行了反相蛋白阵列(RPPA)检测.通过Western印迹和RT-qPCR在几种BC细胞系中证实了RPPA的发现。通过MTT细胞活力和克隆形成测定来测试新的药物组合。
结果：被ERIs下调的信号分子是雌激素受体α（ER-α）和雄激素受体。我们在其他乳腺癌细胞系中证实了这一发现，并表明下调发生在转录水平。我们还发现ERI与他莫昔芬协同作用，乳腺癌的标准治疗方法。
结论：我们的数据表明，将ERIs与激素受体拮抗剂联合使用可以增强其疗效并减少耐药性的出现。
