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

erbB2 阳性乳腺癌肿瘤转移中的 ErbB3-miRNA 轴

基本信息

批准号：
9763330
负责人：
Bolin Liu
金额：
$ 33.63万
依托单位：
LSU HEALTH SCIENCES CENTER
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-01 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9763330
关键词：
1-Phosphatidylinositol 3-Kinase AKT Signaling Pathway Attenuated Bioinformatics Blocking Antibodies Breast Cancer Cell Breast Cancer Patient Breast cancer metastasis Cancer Biology Cell Survival Clinical Data Development Distant Metastasis Down-Regulation Drug resistance ERBB2 gene Ectopic Expression Epigenetic Process Epithelial Epithelium Genes Goals Human In Vitro Light Literature Malignant Neoplasms Mammary Neoplasms Mediating Mediator of activation protein Mesenchymal Metastatic Neoplasm to the Lung Methylation MicroRNAs Modeling Molecular Mouse Mammary Tumor Virus Neoplasm Metastasis Oncogenic Outcome Pathway interactions Patient-Focused Outcomes Patients Play Prospective cohort Retrospective cohort Role Signal Transduction Testing Transgenic Mice Trastuzumab Treatment Efficacy Treatment Failure Vimentin base breast cancer progression cancer therapy cohort combinatorial epigenetic regulation erbB-2 Receptor gain of function histone modification improved in vivo inhibitor/antagonist insight lapatinib loss of function malignant breast neoplasm novel novel strategies novel therapeutics outcome forecast overexpression prevent promoter receptor receptor function slug small hairpin RNA src-Family Kinases survivin targeted agent targeted treatment therapeutic target tumor

项目摘要

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.

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。