ErbB3-miRNA axis in tumor metastasis of erbB2-positive breast cancer

ErbB3受体的高表达与乳腺癌远处转移增加相关 ErbB2(HER2/neu)的扩增和/或过表达，发生在大约25%-30%的侵袭性 乳腺癌与乳腺癌患者的预后不良密切相关。ErbB3 受体在乳腺癌中频繁共表达并与erbB2相互作用激活致癌 信号转导，尤其是PI-3K/Akt通路和Src激酶。ErbB3作为erbB2的共同受体 在erbB2过表达(erbB2+)乳腺癌的发生发展中起关键作用。我们最近的数据 揭示了erbB3的过度表达减少，并抑制了erbB3的信号转导 ShRNA、抗erbB3封闭抗体或Akt抑制剂可增加miR-203和miR-203的水平。 542-3p在erbB2+乳腺癌细胞中表达。有趣的是，miR-203和miR-542-3p都被鉴定为 肿瘤抑制miRNAs，在不同的人类中由于启动子甲基化而经常下调 癌症，包括乳腺癌。生物信息学分析表明miR-203和/或miR-542-3P是靶基因 包括Survivin、ZEB1、ZEB2、Snail1和/或Slug在内的几个关键基因与耐药性有关， 上皮-间充质转化(EMT)与肿瘤转移。我们还发现了一个增强的表达 ZEB1、Snail1、Slug和Vimentin对erbB2+乳腺癌细胞中erbB3异位表达的影响因此，我们 假设erbB3信号激活通过以下途径促进erbB2+乳腺癌转移 抑癌基因miR-203/miR-542-3p的表观遗传沉默及对erbB3的有效抑制 将通过诱导miR-203/miR-542-3p显著抑制肿瘤转移。我们打算定义miR- 203和miR-542-3p作为erbB3信号转导的关键下游介导物增强乳腺癌的转移潜能 通过上调EMT标记上调ERBB2+乳腺癌细胞；并寻找新的策略/药物抑制 通过诱导miR-203/miR-542-3p来预防或减轻erbB2+乳腺癌的转移。

Elevated expression of erbB3 receptor correlates with increased distant metastasis of breast cancers with amplification and/or overexpression of erbB2 (HER2/neu), which occur in approximately 25-30% of invasive breast cancers and are significantly associated with a worse prognosis in breast cancer patients. The erbB3 receptor frequently co-expresses and interacts with erbB2 in breast cancer to activate the oncogenic signaling, especially the PI-3K/Akt pathway and Src kinase. ErbB3 serves as a co-receptor of erbB2 and plays a critical role in the development of erbB2-overexpressing (erbB2+) breast cancer. Our recent data reveal that overexpression of erbB3 decreases, and inhibition of erbB3 signaling with an erbB3 specific shRNA, an anti-erbB3 blocking antibody (Ab), or an Akt inhibitor increases the levels of miR-203 and miR- 542-3p in erbB2+ breast cancer cells. Interestingly, both miR-203 and miR-542-3p have been identified as tumor suppressive miRNAs, and are frequently downregulated due to promoter methylation in various human cancers, including breast cancer. Bioinformatics analysis suggests that miR-203 and/or miR-542-3p target several critical genes, including Survivin, ZEB1, ZEB2, Snail1, and/or Slug, responsible for drug resistance, epithelial-mesenchymal transition (EMT), and tumor metastasis. We also discover an enhanced expression of ZEB1, Snail1, Slug, and Vimentin upon ectopic expression of erbB3 in erbB2+ breast cancer cells. Thus, we hypothesize that activation of erbB3 signaling promotes erbB2+ breast cancer metastasis via epigenetic silencing of the tumor suppressive miR-203/miR-542-3p and effective inhibition of erbB3 will significantly suppress metastasis via induction of miR-203/miR-542-3p. We intend to define miR- 203 and miR-542-3p as the key downstream mediators of erbB3 signaling to enhance metastatic potential of erbB2+ breast cancer cells by upregulating the EMT markers; and identify novel strategy/agents inhibiting erbB3 to prevent or attenuate erbB2+ breast cancer metastasis via induction of miR-203/miR-542-3p.