Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02115, USA.
J Biol Chem. 2011 Aug 26;286(34):29734-47. doi: 10.1074/jbc.M111.220939. Epub 2011 Jul 1.
Human epidermal growth factor receptor 2 (HER2) is overexpressed in 20-25% of breast cancers. Increased HER2 expression is an adverse prognostic factor and correlates with decreased patient survival. HER2-positive (HER2(+)) breast cancer is treated with trastuzumab. Unfortunately, some patients are intrinsically refractory to therapy, and many who do respond initially become resistant within 1 year. Understanding the molecular mechanisms underlying HER2 signaling and trastuzumab resistance is essential to reduce breast cancer mortality. IQGAP1 is a ubiquitously expressed scaffold protein that contains multiple protein interaction domains. By regulating its binding partners IQGAP1 integrates signaling pathways, several of which contribute to breast tumorigenesis. We show here that IQGAP1 is overexpressed in HER2(+) breast cancer tissue and binds directly to HER2. Knockdown of IQGAP1 decreases HER2 expression, phosphorylation, signaling, and HER2-stimulated cell proliferation, effects that are all reversed by reconstituting cells with IQGAP1. Reducing IQGAP1 up-regulates p27, and blocking this increase attenuates the growth inhibitory effects of IQGAP1 knockdown. Importantly, IQGAP1 is overexpressed in trastuzumab-resistant breast epithelial cells, and reducing IQGAP1 both augments the inhibitory effects of trastuzumab and restores trastuzumab sensitivity to trastuzumab-resistant SkBR3 cells. These data suggest that inhibiting IQGAP1 function may represent a rational strategy for treating HER2(+) breast carcinoma.
人表皮生长因子受体 2（HER2）在 20-25%的乳腺癌中过度表达。HER2 表达增加是一个不良的预后因素，并与患者生存率降低相关。HER2 阳性（HER2(+））乳腺癌采用曲妥珠单抗治疗。不幸的是，一些患者对治疗具有内在的耐药性，许多最初对治疗有反应的患者在 1 年内会产生耐药性。了解 HER2 信号转导和曲妥珠单抗耐药的分子机制对于降低乳腺癌死亡率至关重要。IQGAP1 是一种广泛表达的支架蛋白，含有多个蛋白相互作用结构域。通过调节其结合伴侣，IQGAP1 整合信号通路，其中一些通路有助于乳腺癌的发生。我们在这里显示，IQGAP1 在 HER2(+)乳腺癌组织中过度表达，并直接与 HER2 结合。IQGAP1 的敲低会降低 HER2 的表达、磷酸化、信号转导和 HER2 刺激的细胞增殖，这些效应都可以通过用 IQGAP1 重建细胞来逆转。降低 IQGAP1 会上调 p27，而阻断这种增加会减弱 IQGAP1 敲低的生长抑制作用。重要的是，IQGAP1 在曲妥珠单抗耐药的乳腺上皮细胞中过度表达，降低 IQGAP1 不仅增强了曲妥珠单抗的抑制作用，而且恢复了曲妥珠单抗对曲妥珠单抗耐药的 SkBR3 细胞的敏感性。这些数据表明，抑制 IQGAP1 功能可能是治疗 HER2(+)乳腺癌的合理策略。
