ERBB3-miRNAs信号通路轴在ERBB2阳性乳腺癌转移中的作用及机制研究

Elevated expression of ERBB3 receptor correlates with increased distant metastasis of breast cancers with amplification and/or overexpression of ERBB2 (HER2/neu), which the underlying molecular mechanism remains unclear. Based on our previous study, we hypothesize that activation of ERBB3 signaling promotes ERBB2+ breast cancer metastasis via epigenetic silencing of the tumor suppressive miR-203/miR-542-3p, which in turn results in altered expression of EMT regulators. We will focus our study on: 1) unveiling the molecular mechanism underlying epigenetic regulation of expression of miR-203 and miR-542-3p by ERBB3 signaling; 2) investigating the relativity between expression of ERBB3, miR-203, miR-542-3p and metastasis of ERBB2+ breast cancer by analysis of clinical samples; 3) exploring whether effective inhibition of ERBB3 signaling will significantly suppress metastasis of ERBB2+ breast cancer. The fulfillment of current proposed study will not only add knowledge to our understanding of molecular mechanism of breast cancer metastasis, but also offer a theoretic basis as well as guidance for development of new therapy for metastatic breast cancer.

ERBB3高表达的ERBB2阳性乳腺癌多呈侵袭性生长并好发转移，但其确切的分子机制尚未完全阐明。基于自身前期的研究工作基础，我们在本申请项目中提出工作假说认为：ERBB3信号通路的激活可能通过表观遗传修饰的介导以下调miR-203和miR-542-3p的表达，并进而影响其EMT调控相关靶基因的表达以促进ERBB2阳性乳腺癌的侵袭性生长和转移。我们将重点研究：1）ERBB3信号通路调控miR-203和miR-542-3p表达的表观遗传相关分子机制；2）通过临床病例标本的分析进一步明确ERBB3、miR-203和miR-542-3p与ERBB2阳性乳腺癌病人转移的预后相关性；3) 拟在整体动物水平初步探索是否靶向阻断ERBB3信号通路可有效抑制ERBB2阳性乳腺癌的转移。课题的实施不仅有助于拓展我们对乳腺癌转移的分子机制的认识，同时也对开发乳腺癌转移的临床靶向治疗新措施具有重要的实际指导意义。

ERBB3高表达的ERBB2阳性乳腺癌多呈侵袭性生长并好发转移，但其确切的分子机制大多不详。本项目于国内外首次分别从体外分子和细胞水平、临床病例分析和整体动物实验三个层探讨了ERBB3-miRNAs这一信号通路在促进ERBB2阳性乳腺癌的侵袭性生长和转移中发挥重要的生物学作用及其相关的分子机制以及初步的靶向治疗效果。我们的研究发现，ERBB3可通过激活下游PI3K/Akt信号转导通路以促进ERBB2阳性乳腺癌细胞EMT表型改变和侵袭及迁移能力；初步的机制探讨表明，ERBB3过表达可能主要通过促进DNMT3A的表达诱导miR-203基因启动子区的高甲基化以下调其表达，进一步通过其介导的ZEB1高表达以调控ERBB2阳性乳腺癌细胞的EMT、侵袭及迁移表型。临床病例标本的分析首次揭示了ERBB2阳性乳腺癌中ERBB3 mRNA的表达水平显著高于、而miR-203和miR-542-3p表达水平则显著低于癌旁对照组织；ERBB3 mRNA的表达水平与miR-203和miR-542-3p的表达水平呈显著负相关性；首次发现约24.39%（50/205）的ERBB2阳性乳腺癌患者存在miR-203启动子区的高甲基化。动物实验的探索首次证实，VPA可显著抑制ERBB3过表达ERBB2阳性乳腺癌肺转移瘤的形成，这为后续拓展ERBB2阳性乳腺癌转移的早期临床干预新措施奠定了实验基础。综上，本项目已基本达到原定的主要研究目标；研究所获得的成果进一步提升了我们对乳腺癌转移的分子机制的认知水平，同时也必将对未来临床乳腺癌转移早期预防和更加有效的治疗措施的开发具有重要的实际指导意义。