Trastuzumab targets the HER2 receptor on breast cancer cells to attenuate HER2-driven tumor growth. However, resistance to trastuzumab-based therapy remains a major clinical problem for women with HER2+ breast cancer. Breast cancer stem cells (BCSCs) are suggested to be responsible for drug resistance and tumor recurrence. Notch signaling has been shown to promote BCSC survival and self-renewal. Trastuzumab-resistant cells have increased Notch-1 expression. Notch signaling drives cell proliferation in vitro and is required for tumor recurrence in vivo. We demonstrate herein a mechanism by which Notch-1 is required for trastuzumab resistance by repressing PTEN expression to contribute to activation of ERK1/2 signaling. Furthermore, Notch-1-mediated inhibition of PTEN is necessary for BCSC survival in vitro and in vivo. Inhibition of MEK1/2-ERK1/2 signaling in trastuzumab-resistant breast cancer cells mimics effects of Notch-1 knockdown on bulk cell proliferation and BCSC survival. These findings suggest that Notch-1 contributes to trastuzumab resistance by repressing PTEN and this may lead to hyperactivation of ERK1/2 signaling. Furthermore, high Notch-1 and low PTEN mRNA expression may predict poorer overall survival in women with breast cancer. Notch-1 protein expression predicts poorer survival in women with HER2+ breast cancer. These results support a potential future clinical trial combining anti-Notch-1 and anti-MEK/ERK therapy for trastuzumab-resistant breast cancer.

中文翻译：

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Notch-1-PTEN-ERK1/2 信号轴促进 HER2+ 乳腺癌细胞增殖和干细胞存活。

曲妥珠单抗靶向乳腺癌细胞上的 HER2 受体，以减弱 HER2 驱动的肿瘤生长。然而，对基于曲妥珠单抗的治疗的耐药性仍然是 HER2+ 乳腺癌女性的主要临床问题。乳腺癌干细胞（BCSCs）被认为是导致耐药性和肿瘤复发的原因。Notch 信号已被证明可以促进 BCSC 的存活和自我更新。曲妥珠单抗耐药细胞增加了 Notch-1 的表达。Notch 信号在体外驱动细胞增殖，是体内肿瘤复发所必需的。我们在此证明了一种机制，通过抑制 PTEN 表达以促进 ERK1/2 信号传导的激活，曲妥珠单抗耐药需要 Notch-1。此外，Notch-1 介导的 PTEN 抑制是 BCSC 在体外和体内存活所必需的。抑制曲妥珠单抗耐药乳腺癌细胞中的 MEK1/2-ERK1/2 信号传导模拟 Notch-1 敲低对大量细胞增殖和 BCSC 存活的影响。这些发现表明，Notch-1 通过抑制 PTEN 导致曲妥珠单抗耐药，这可能导致 ERK1/2 信号的过度激活。此外，高 Notch-1 和低 PTEN mRNA 表达可能预示着乳腺癌女性的总体生存期较差。Notch-1 蛋白表达预示着 HER2+ 乳腺癌女性的生存期较差。这些结果支持了一项潜在的未来临床试验，该试验将抗 Notch-1 和抗 MEK/ERK 疗法结合起来治疗曲妥珠单抗耐药性乳腺癌。这些发现表明，Notch-1 通过抑制 PTEN 导致曲妥珠单抗耐药，这可能导致 ERK1/2 信号的过度激活。此外，高 Notch-1 和低 PTEN mRNA 表达可能预示着乳腺癌女性的总体生存期较差。Notch-1 蛋白表达预示着 HER2+ 乳腺癌女性的生存期较差。这些结果支持了一项潜在的未来临床试验，该试验将抗 Notch-1 和抗 MEK/ERK 疗法结合起来治疗曲妥珠单抗耐药性乳腺癌。这些发现表明，Notch-1 通过抑制 PTEN 导致曲妥珠单抗耐药，这可能导致 ERK1/2 信号的过度激活。此外，高 Notch-1 和低 PTEN mRNA 表达可能预示着乳腺癌女性的总体生存期较差。Notch-1 蛋白表达预示着 HER2+ 乳腺癌女性的生存期较差。这些结果支持了一项潜在的未来临床试验，该试验将抗 Notch-1 和抗 MEK/ERK 疗法结合起来治疗曲妥珠单抗耐药性乳腺癌。