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

erbB 3受体表达升高与乳腺癌远处转移增加相关， erbB 2（HER 2/neu）扩增和/或过表达，发生在大约25-30%的侵袭性肿瘤中。 与乳腺癌患者的预后不良显著相关。erbB3 受体在乳腺癌中经常与erbB 2共表达并相互作用，以激活癌基因 信号转导，尤其是PI-3 K/Akt通路和Src激酶。ErbB 3作为erbB 2的共受体， 在erbB 2过表达（erbB 2+）乳腺癌的发展中起着关键作用。我们最近的数据 显示erbB 3的过度表达减少，并且用erbB 3特异性抑制erbB 3信号传导， shRNA、抗erbB 3阻断抗体（Ab）或Akt抑制剂增加miR-203和miR-204的水平。 erbB 2+乳腺癌细胞中的542- 3 p。有趣的是，miR-203和miR-542- 3 p都被鉴定为 肿瘤抑制性miRNAs，并且在各种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- 3 p靶向 几个关键基因，包括Survivin、ZEB 1、ZEB 2、Snail 1和/或Slug，负责耐药性， 上皮-间质转化（EMT）和肿瘤转移。我们还发现， ZEB 1、Snail 1、Slug和波形蛋白对erbB 2+乳腺癌细胞中erbB 3异位表达的影响因此我们 假设erbB 3信号传导激活通过以下途径促进erbB 2+乳腺癌转移： 肿瘤抑制性miR-203/miR-542- 3 p的表观遗传沉默和erbB 3的有效抑制 将通过诱导miR-203/miR-542- 3 p显著抑制转移。我们打算定义miR- 203和miR-542- 3 p作为erbB 3信号传导的关键下游介质，以增强肿瘤的转移潜力。 通过上调EMT标志物来抑制erbB 2+乳腺癌细胞;并鉴定抑制erbB 2+乳腺癌细胞的新策略/试剂。 erbB 3通过诱导miR-203/miR-542- 3 p预防或减弱erbB 2+乳腺癌转移。

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.