YAP increases response to Trastuzumab in HER2-positive Breast Cancer by enhancing P73-induced apoptosis.
YAP increases response to Trastuzumab in HER2-positive Breast Cancer by enhancing P73-induced apoptosis.
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DOI：
10.7150/jca.48535
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发表时间：
2020
影响因子：
3.9
通讯作者：
Gao H
中科院分区：
文献类型：
--
作者：
Cao L;Yao M;Sasano H;Sun PL;Gao H
Yes相关蛋白（雅普）在乳腺癌发生和发展中的作用仍存在争议。与此同时，对曲妥珠单抗（一种在化疗后施用的常见乳腺癌治疗）的治疗耐药性的发展是HER 2阳性乳腺癌治疗中的重大挑战。因此，我们分析了雅普在体外HER 2阳性乳腺癌细胞中曲妥珠单抗耐药中的作用，并通过免疫组化评估了雅普和相关蛋白在患者来源的乳腺癌组织中的状态。在BT474-TS（曲妥珠单抗敏感）和BT474-TR（曲妥珠单抗耐药）细胞中均观察到雅普表达。用曲妥珠单抗处理增加BT474-TS细胞中核-YAP（N-YAP）的表达，而BT474-TR细胞显示在曲妥珠单抗处理后N-YAP表达降低。雅普沉默显著降低BT474-TS细胞中曲妥珠单抗诱导的抑制作用。YAP沉默的细胞还显示曲妥珠单抗治疗后细胞凋亡减少和p73水平显著降低。联合蛋白激酶B（AKT）激动剂-曲妥珠单抗处理显著抑制BT474-TR细胞增殖，导致N-YAP和p73表达增加，以及凋亡。在紫杉醇、多柔比星和环磷酰胺（TAC）治疗组和多西他赛、卡铂和曲妥珠单抗（TCbH）治疗组中，病理学完全缓解（pCR）比率与活检标本中的p-AKT状态呈负相关，而雅普和p73状态与TCbH组活检标本中的pCR比率呈正相关。我们的研究结果表明，雅普参与了HER 2阳性乳腺癌细胞的曲妥珠单抗耐药，雅普和AKT可能被开发为HER 2阳性乳腺癌患者新辅助曲妥珠单抗治疗的预后标志物。
The role of the Yes-associated protein (YAP) in oncogenesis and progression of breast cancer remains controversial. Meanwhile, development of therapeutic resistance to trastuzumab, a common breast cancer treatment administered after chemotherapy, is a significant challenge in the treatment of HER2-positive breast cancer. We, therefore, analyzed the role of YAP in trastuzumab resistance in HER2-positive-breast carcinoma cells in vitro and evaluated the status of YAP and related proteins in patient-derived breast carcinoma tissues by immunohistochemistry. YAP expression was observed in both BT474-TS (trastuzumab-sensitive) and BT474-TR (trastuzumab-resistant) cells. Treatment with trastuzumab increased expression of nuclear-YAP (N-YAP) in BT474-TS cells, whereas BT474-TR cells showed a decrease in N-YAP expression following trastuzumab treatment. YAP silencing significantly reduced trastuzumab-induced inhibitory effects in BT474-TS cells. YAP-silenced cells also showed decreased apoptosis and significantly lower p73 levels following trastuzumab treatment. Combined protein kinase B (AKT) inhibitor-trastuzumab treatment significantly inhibited BT474-TR cell proliferation, resulting in increased N-YAP and p73 expression, as well as apoptosis. In both paclitaxel, doxorubicin and cyclophosphamide (TAC)-treated, and docetaxel, carboplatin, and trastuzumab (TCbH)-treated groups; the pathological complete response (pCR) ratios were inversely correlated with p-AKT status in biopsy specimens, while YAP and p73 status were positively correlated with the pCR ratio in the biopsy specimens of the TCbH group. Our results show that YAP is involved in trastuzumab resistance in HER2-positive breast carcinoma cells and that YAP and AKT may be developed as prognostic markers of neoadjuvant trastuzumab therapy in patients with HER2-positive breast cancer.