Survivin-targeting miRNAs in erbB3 promotion of erbB2-positive breast cancer

描述(申请人提供)：erbB2(或HER2/neu)的扩增和/或过表达发生在大约25%-30%的浸润性乳腺癌中，并与较差的预后显著相关。机制研究表明，对治疗的抵抗力增加和转移潜能增强是erbB2促进乳腺肿瘤发生的主要机制。然而，erbB2并不是单独起作用的。另一个密切相关的受体erbB3经常与erbB2共表达并相互作用，激活致癌信号，如PI-3K/Akt通路等，从而促进乳腺癌的进展。然而，在erbB2阳性(erbB2+)乳腺癌中，erbB3信号的关键下游介体仍然难以捉摸。我们已经报道，erbB3/PI-3K/Akt信号转导通路通过上调凋亡抑制因子Survivin的表达，使erbB2+乳腺癌细胞产生紫杉醇耐药。我们最近对其潜在机制的研究发现，在erbB2+乳腺癌细胞中，用shRNA、封闭抗体或Akt抑制剂抑制erbB3信号转导，可以降低和增强两种Survivin靶向miRNAs miR-203和miR-542-3p的表达。有趣的是，miR-203和miR-542-3p都被鉴定为肿瘤抑制的miRNAs，并且由于启动子甲基化在包括乳腺癌在内的各种癌症中经常下调。生物信息学分析表明，除了Survivin，这两个miRNAs还共同靶向一组关键基因，如ABCG2、ZEB2和Snail，这些基因与耐药和肿瘤转移有关。因此，我们假设，erbB3信号的激活通过表观遗传沉默靶向Survivin的miR-203和miR-542-3p来促进erbB2+乳腺癌的进展。本研究旨在探讨erbB3信号诱导miR-203/miR-542-3p下调的分子基础，并确定miRNA替代治疗联合紫杉醇对erbB2+乳腺癌的抗肿瘤活性。

DESCRIPTION (provided by applicant): Amplification and/or overexpression of erbB2 (or HER2/neu) occur in approximately 25-30% of invasive breast cancer and are significantly associated with a worse prognosis. Mechanistic studies suggest that increased resistance to treatment and enhanced metastatic potential are the major mechanism by which erbB2 contributes to breast tumorigenesis. However, erbB2 does not act in isolation. Another closely related receptor erbB3 frequently co-expresses and interacts with erbB2 to activate the oncogenic signaling, such as PI-3K/Akt pathway and others, and subsequently promote breast cancer progression. Nonetheless, the crucial downstream mediators of erbB3 signaling in erbB2-positive (erbB2+) breast cancer remain elusive. We have reported that the erbB3/PI-3K/Akt signaling confers paclitaxel resistance in erbB2+ breast cancer cells via specific upregulation of Survivin, a vital inhibitor of apoptosis. Our recent studies on the underlying mechanism discover that elevated expression of erbB3 decreases and inhibition of erbB3 signaling with shRNA, a blocking antibody (Ab), or an Akt inhibitor increases the expression of two Survivin-targeting miRNAs, 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 cancers, including breast cancer. Bioinformatic analysis suggests that in addition to Survivin, these two miRNAs also co-target a cohort of critical genes, such as ABCG2, ZEB2, and Snail, responsible for drug resistance and tumor metastasis. Thus, we hypothesize that activation of erbB3 signaling promotes erbB2+ breast cancer progression via epigenetic silencing of the Survivin-targeting miR-203 and miR-542-3p. This proposal aims to explore the molecular basis of erbB3 signaling-induced reduction of miR-203/miR-542-3p, and determine the anti-tumor activity of miRNA-replacement therapy in combination with paclitaxel against erbB2+ breast cancer.