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

生存素靶向 miRNA 在 erbB3 促进 erbB2 阳性乳腺癌中的作用

基本信息

批准号：
8804923
负责人：
Bolin Liu
金额：
$ 7.76万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-02-12 至 2016-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8804923
关键词：
1-Phosphatidylinositol 3-Kinase ABCG2 gene Apoptosis Inhibitor Bioinformatics Blocking Antibodies Breast Cancer Cell Breast Cancer Patient Breast Cancer Treatment Cancer Biology Clinical Data Development Down-Regulation Drug resistance ERBB2 gene Epigenetic Process Genes Health Malignant Neoplasms Mediating Mediator of activation protein Methylation MicroRNAs Molecular Neoplasm Metastasis Oncogenic Paclitaxel Pathway interactions Play Replacement Therapy Reporting Resistance Role Signal Transduction Snails Testing Therapeutic Therapeutic Agents Treatment Efficacy Up-Regulation Work base breast tumorigenesis cancer therapy cohort inhibitor/antagonist malignant breast neoplasm novel strategies outcome forecast overexpression promoter public health relevance receptor small hairpin RNA src-Family Kinases survivin tumor tumor progression

项目摘要

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.

描述（申请人提供）：erbB 2（或HER 2/neu）扩增和/或过表达发生在约25-30%的浸润性乳腺癌中，并与预后不良显著相关。机制研究表明，对治疗的耐药性增加和转移潜能增强是erbB 2促进乳腺肿瘤发生的主要机制。然而，erbB 2并不是孤立地起作用。另一个密切相关的受体erbB 3经常与erbB 2共表达并相互作用以激活致癌信号传导，如PI-3 K/Akt通路等，并随后促进乳腺癌进展。尽管如此，在erbB 2阳性（erbB 2+）乳腺癌中erbB 3信号传导的关键下游介质仍然难以捉摸。我们已经报道了erbB 3/PI-3 K/Akt信号通过特异性上调Survivin（一种重要的凋亡抑制剂）赋予erbB 2+乳腺癌细胞紫杉醇耐药性。我们最近对相关机制的研究发现，erbB 2+乳腺癌细胞中erbB 3的高表达降低，而用shRNA、阻断抗体（Ab）或Akt抑制剂抑制erbB 3信号传导增加了两种靶向Survivin的miRNAs，miR-203和miR-542- 3 p的表达。有趣的是，miR-203和miR-542- 3 p都已被鉴定为肿瘤抑制性miRNA，并且由于各种癌症（包括乳腺癌）中的启动子甲基化而经常下调。生物信息学分析表明，除了Survivin，这两种miRNA还共同靶向一组关键基因，如ABCG 2，ZEB 2和Snail，负责耐药性和肿瘤转移。因此，我们假设erbB 3信号的激活通过Survivin靶向miR-203和miR-542- 3 p的表观遗传沉默促进erbB 2+乳腺癌进展。本研究旨在探索erbB 3信号转导诱导miR-203/miR-542- 3 p减少的分子基础，并确定miRNA替代疗法联合紫杉醇对erbB 2+乳腺癌的抗肿瘤活性。