ERBB3/HER3 and ERBB2/HER2 duet in mammary development and breast cancer
ERBB3/HER3 and ERBB2/HER2 duet in mammary development and breast cancer
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DOI：
10.1007/s10911-008-9083-7
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发表时间：
2008-06-01
影响因子：
2.5
通讯作者：
Stern, David F.
中科院分区：
文献类型：
--
作者：
Stern, David F.
ERBB 3/HER 3是表皮生长因子受体（ERBB）家族的四个成员之一。它通过与配体Neuregulin-1和Neuregulin-2结合而被激活。由于ERBB 3缺乏内在激酶活性，因此通过与EGFR、ERBB 2和ERBB 4形成异二聚体来进行信号转导。ERBB 3是一种信号传导专家，因为它具有磷酸肌醇3'激酶的p85 SH 2衔接子亚基的六个结合位点。这些脂质激酶协调代谢、细胞大小、增殖、存活和血管生成的调节。毫不奇怪，ERBB 3信号传导与癌症病因和进展有关。在乳腺癌中，ERBB 2和ERBB 3的伙伴关系可能对ERBB 2扩增的癌症的侵袭性至关重要，并可能导致对治疗的预先存在和获得性耐药性。这种伙伴关系为改善ERBB靶向药物的疗效创造了机会，通过二聚化抑制剂干扰ERBB 2与ERBB 3的偶联，并通过使用靶向ERBB 3激活的AKT依赖性途径的治疗化合物。通过更好地了解ERBB如何在正常乳腺过程中调节和部署，可以确定其他治疗机会。使用小鼠模型的工作已经确定了由四种ERBB中的每一种调控的主要过程，这对理解乳腺癌病因学以及最终开发更好的预后，预测和治疗工具具有实际意义。
ERBB3/HER3 is one of the four members of the epidermal growth factor receptor (ERBB) family. It is activated by binding to ligands Neuregulin-1 and Neuregulin-2. Since ERBB3 lacks intrinsic kinase activity, signal transduction occurs through formation of heterodimers with EGFR, ERBB2, and ERBB4. ERBB3 is a signaling specialist since it has six binding sites for the p85 SH2 adapter subunit of phosphoinositide 3' kinases. These lipid kinases coordinate regulation of metabolism, cell size, proliferation, survival, and angiogenesis. Not surprisingly, ERBB3 signaling has been linked to cancer etiology and progression. In breast cancer, the partnership of ERBB2 and ERBB3 may be crucial for the aggressive properties of cancers with ERBB2 amplification, and may contribute to pre-existing and acquired resistance to therapy. This partnership creates opportunities for improving efficacy of ERBB-targeted pharmaceuticals, by interfering with coupling of ERBB2 to ERBB3 through dimerization inhibitors, and by use of therapeutic compounds that target AKT-dependent pathways activated through ERBB3. Additional therapeutic opportunities may be identified through better understanding of how ERBBs are regulated and deployed in normal mammary gland processes. Work using mouse models has identified the main processes regulated by each of the four ERBBs, which has practical implications in understanding breast cancer etiology, and eventual development of better prognostic, predictive, and therapeutic tools.