Trastuzumab resistance in HER2+ breast cancer (BC) is the major reason leading to poor prognosis of BC patients. Oncogenic gene overexpression or aberrant activation of tyrosine kinase SRC is identified to be the key modulator of trastuzumab response. However, the detailed regulatory mechanisms underlying SRC activation-associated trastuzumab resistance remain poorly understood. In the present study, we discover that SRC-mediated YAP1 tyrosine phosphorylation facilitates its interaction with transcription factor AP-2 alpha (activating enhancer binding protein 2 alpha, TFAP2A), which in turn promotes YAP1/TEAD-TFAP2A (YTT) complex-associated transcriptional outputs, thereby conferring trastuzumab resistance in HER2+ BC. Inhibition of SRC kinase activity or disruption of YTT complex sensitizes cells to trastuzumab treatment in vitro and in vivo. Additionally, we also identify YTT complex co-occupies the regulatory regions of a series of genes related to trastuzumab resistance and directly regulates their transcriptions, including , , and . Moreover, YTT-mediated transcriptional regulation is coordinated by SRC kinase activity. Taken together, our study reveals that SRC-mediated YTT complex formation and transcriptions are responsible for multiple mechanisms associated with trastuzumab resistance. Therefore, targeting HER2 signaling in combination with the inhibition of YTT-associated transcriptional outputs could serve as the treatment strategy to overcome trastuzumab resistance caused by SRC activation.

中文翻译：

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酪氨酸磷酸化介导的 YAP1-TFAP2A 相互作用协调 HER2+ 乳腺癌中的转录和曲妥珠单抗耐药性

HER2+乳腺癌（BC）的曲妥珠单抗耐药是导致BC患者预后不良的主要原因。致癌基因过度表达或酪氨酸激酶 SRC 的异常激活被确定为曲妥珠单抗反应的关键调节剂。然而，SRC 激活相关的曲妥珠单抗耐药性背后的详细调节机制仍然知之甚少。在本研究中，我们发现SRC介导的YAP1酪氨酸磷酸化促进其与转录因子AP-2α（激活增强子结合蛋白2α，TFAP2A）的相互作用，进而促进YAP1/TEAD-TFAP2A（YTT）复合物相关转录输出，从而赋予 HER2+ BC 曲妥珠单抗耐药性。SRC 激酶活性的抑制或 YTT 复合物的破坏使细胞在体外和体内对曲妥珠单抗治疗敏感。此外，我们还发现YTT复合物共同占据一系列与曲妥珠单抗耐药相关的基因的调节区域，并直接调节它们的转录，包括 、 和 。此外，YTT 介导的转录调节是由 SRC 激酶活性协调的。综上所述，我们的研究表明，SRC 介导的 YTT 复合物形成和转录负责与曲妥珠单抗耐药性相关的多种机制。因此，靶向 HER2 信号传导结合抑制 YTT 相关转录输出可以作为克服 SRC 激活引起的曲妥珠单抗耐药性的治疗策略。