权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

MYC/miR-18a-5p/HIF1A regulatory network confers drug resistance to breast cancer

MYC/miR-18a-5p/HIF1A调控网络赋予乳腺癌耐药性

基本信息

批准号：
9251783
负责人：
Meiyun Fan
金额：
$ 7.6万
依托单位：
UNIVERSITY OF TENNESSEE HEALTH SCI CTR
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：
2016-04-01 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9251783
关键词：
Affect Brain Breast Cancer Cell Breast Cancer Patient Cause of Death Cell Proliferation Cell Survival Cells Data Down-Regulation Drug resistance Drug-sensitive Enzymes Event Future G6PD gene Gene Expression Genetic Transcription Glucose HIF1A gene Homeostasis Hypoxia Intervention Knowledge Lung Mediating Metabolic Metabolism MicroRNAs Molecular NADP Neoplasm Metastasis Oncoproteins Outcome Study Patients Phenotype Play Predisposition Production Regulation Relapse Research Resistance Role Testing The Cancer Genome Atlas Therapeutic Uses anticancer treatment cancer therapy chemotherapeutic agent chemotherapy clinically relevant clinically significant cytotoxicity derepression design experience genetic signature genome-wide improved malignant breast neoplasm neoplastic cell novel novel strategies prevent public health relevance response standard care tumor

项目摘要

DESCRIPTION (provided by applicant): Metastatic relapse is the leading cause of death for patients with basal-like breast cancer (BLBC), the most aggressive subtype that accounts for ~15% of all breast cancers. BLBC tends to affect younger patients and metastasize to lung and brain. Systematic chemotherapy is the standard treatment for patients with BLBC tumors. Despite initial high response rates to chemotherapy, manifested by tumor regression, most patients (~85%) experience metastatic relapse within 10 years. Currently there is no effective way to treat or prevent metastatic relapse because we do not fully understand what enables tumor cells to escape cytotoxicity of chemotherapy. Our recent studies and analysis of The Cancer Genome Atlas (TCGA) data suggest that two distinct phenotypic states, MYC-driven proliferative and drug-sensitive state and HIF1A-driven invasive and drug-resistant state, coexist among BLBC tumor cells. We found that miR-18a-5p plays a key role in regulating phenotypic state of BLBC cells by suppressing HIF1A activation, and derepression of HIF1A due to miR-18a-5p downregulation is sufficient to convert tumor cells into a drug resistant state. We propose to examine whether increasing cellular content of miR-18a-5p to suppress HIF1A activation or inhibiting metabolic enzymes regulated by HIF1A can be used for therapeutic purpose to increase chemosensitivity of BLBC cells. The results from these studies will contribute to a broader understanding of the function of miRNAs in regulating cell phenotype, and advance our understanding of HIF1A-mediated drug resistance.

描述（由申请人提供）：转移性复发是基底细胞样乳腺癌（BLBC）患者的主要死亡原因，BLBC是最具侵袭性的亚型，占所有乳腺癌的约15%。BLBC倾向于影响年轻患者并转移到肺和脑。全身化疗是BLBC肿瘤患者的标准治疗方法。尽管最初对化疗的反应率很高，表现为肿瘤消退，但大多数患者（约85%）在10年内发生转移性复发。目前还没有有效的方法来治疗或预防转移复发，因为我们不完全了解是什么使肿瘤细胞逃避化疗的细胞毒性。我们最近的研究和对癌症基因组图谱（TCGA）数据的分析表明，两种不同的表型状态，MYC驱动的增殖和药物敏感状态和HIF 1A驱动的侵袭和耐药状态，在BLBC肿瘤细胞中共存。我们发现，miR-18 a-5 p通过抑制HIF 1A活化在调节BLBC细胞的表型状态中起关键作用，并且由于miR-18 a-5 p下调而导致的HIF 1A去抑制足以将肿瘤细胞转化为耐药状态。我们建议检查增加miR-18 a-5 p的细胞含量以抑制HIF 1A活化或抑制由HIF 1A调节的代谢酶是否可用于治疗目的以增加BLBC细胞的化学敏感性。这些研究的结果将有助于更广泛地了解miRNAs在调节细胞表型中的功能，并促进我们对HIF 1A介导的耐药性的理解。