Mechanism of chemoresistance mediated by TGF-beta

TGF-β介导的化疗耐药机制

• 批准号: 9324482
• 负责人: Shizhen Emily Wang
• 金额: $ 32.16万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9324482
• 关键词: ATM Signaling Pathway; Accelerometer; Animals; Apoptosis; Binding; Biological Assay; Breast Cancer Cell; Cancer Patient; Cell Cycle; Cells; Clinical; Complex; DNA; DNA Binding; DNA Damage; Development; Disease Progression; Dissection; Down-Regulation; Doxycycline; Drug Controls; Drug resistance; Exhibits; Future; Genes; Genetic Transcription; Goals; Human; Intervention; Link; MADH2 gene; MADH4 gene; MSH2 gene; Malignant Neoplasms; Mediating; Mediator of activation protein; MicroRNAs; Modeling; Molecular; Molecular Profiling; Molecular and Cellular Biology; Monitor; Mutate; Normal Cell; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Poly(ADP-ribose) Polymerases; Process; RNA; RNA Binding; Regulation; Reporter; Reporting; Resistance; Role; Signal Transduction; Staging; TP53 gene; Testing; Therapeutic; Transducers; Transforming Growth Factor beta; Transforming Growth Factor beta Receptors; Transforming Growth Factors; Transplantation; Treatment Efficacy; Tumor Suppressor Proteins; cancer cell; cancer therapy; chemotherapy; chromatin immunoprecipitation; cofactor; cytokine; drug efficacy; experience; in vitro Assay; in vivo; inducible gene expression; inhibitor/antagonist; innovation; insight; knock-down; malignant breast neoplasm; neoplastic cell; new therapeutic target; novel; novel strategies; novel therapeutics; outcome forecast; overexpression; p53-binding protein 1; response; sensor; targeted treatment; therapy resistant; transcription factor; triple-negative invasive breast carcinoma; tumor; tumor growth; tumor xenograft; vector

DESCRIPTION (provided by applicant): Many chemotherapy drugs act against cancer cells by causing damage to the DNA. Resistance to chemotherapy is a major clinical obstacle in cancer treatment. The mechanisms of chemoresistance in cancer patients are not fully understood, leading to urgent needs for determining factors that control drug response and developing novel therapies to enhance the treatment efficacy. Signaling from transforming growth factor (TGF) ß, a tumor suppressor in normal cells, is hijacked in cancer to promote disease progression. In breast cancer, TGF-ß is linked to poor clinical outcomes and chemoresistance through mechanisms that remain largely unknown. Our previous studies indicate that in breast cancer cells, TGF-ß induces microRNAs (miR-21 and miR-181) that target the DNA damage sensors ATM and MSH2, and may therefore regulate cancer response to genotoxic chemotherapy. The goals of this study are to dissect the molecular mechanism of TGF-ß-mediated chemoresistance, and to explore potential therapies to enhance drug efficacy. In Aim 1, TGF-ß action on cell response to various DNA-damaging treatments and to inhibition of poly(ADP-ribose) polymerase (PARP) will be determined in breast cancer cells with different p53 status using established molecular and cellular biology assays. The role of the TGF-ß-regulated miRNAs and the ATM/MSH2 pathways will be determined using gene knockdown and overexpression strategies. In Aim 2, the hypothesis that enhanced SMAD2/3 binding to their RNA targets mediates TGF-ß's functional shift in cancer cells towards inducing miRNA regulation and chemoresistance will be examined. Breast cancer cells expressing various levels of the SMAD2/3 cofactors (i.e., SMAD4, Drosha and p68) will be examined for their dynamic regulation of SMAD2/3 function and TGF-ß effect. In Aim 3, the effect of TGF-ß on chemotherapy response and the mechanism identified in the first two aims will be evaluated in animal tumor models. Novel strategies to therapeutically suppress this TGF-ß function and enhance the treatment efficacy will be explored. This study will enable better understandings of drug resistance and of TGF-ß signaling as both a marker and a target in cancer treatment. Although the mechanism identified herein may have a general application to understanding cancer and defining treatments, our study has added significance for clinically aggressive, hard-to-treat basal- like (mainly triple-negative) breast cancer that often experience active TGF-ß signaling. This study will provide novel insight into the functional switch of TGF-ß in cancer via SMAD2/3-mediated miRNA processing. Understanding TGF-ß-mediated chemoresistance may reveal novel therapeutic targets and strategies that will enhance the chemotherapy efficacy for cancers that lack targets for systemic treatments. Our long-term objectives are to validate this mechanism in primary cancers and establish standard approaches to identify patients suitable for therapies targeting TGF-ß's drug resistant effect, and to understand the global effect of TGF-ß -mediated miRNA dysregulation in human cancer.

描述（由适用提供）：许多化学疗法药物通过损害DNA来对癌细胞起作用。对化学疗法的抗性是癌症治疗中的主要临床障碍。癌症患者化学耐药性的机制尚未完全了解，从而迫切需要确定控制药物反应并开发新疗法以提高治疗效率的因素。在正常细胞中抑制肿瘤的转化生长因子（TGF）的信号传导被劫持在癌症中以促进疾病进展。在乳腺癌中，TGF-ß通过仍然未知的机制与临床结局不良和化学抗性有关。我们先前的研究表明，在乳腺癌细胞中，TGF-β诱导靶向DNA损伤传感器ATM和MSH2的microRNA（miR-21和miR-181），因此可能调节癌症对遗传毒性化学疗法的反应。这项研究的目标是剖析分子机制 TGF-β介导的化学抗性，并探索潜在的疗法以提高药物效率。在AIM 1中，将使用已建立的分子和细胞生物学测定法在不同的p53状态的乳腺癌细胞中确定TGF-β对各种DNA损害治疗的细胞反应和抑制聚（ADP-核糖）聚合酶（PARP）的作用。角色 TGF-ß调节的miRNA和ATM/MSH2途径将使用基因敲低和过表达策略确定。在AIM 2中，将研究介导TGF-ß在癌细胞中介导TGF-ß对诱导miRNA调节和化学抗性的介导的smad2/3结合的假设。将检查表达各种水平的SMAD2/3辅因子（即Smad4，Drosha和P68）的乳腺癌细胞，以动态调节SMAD2/3功能和TGF-ß效应。在AIM 3中，将在动物肿瘤模型中评估TGF-β对化学疗法反应和前两个目标中确定的机制的影响。将探索热抑制此TGF-ß功能并提高治疗效率的新型策略。这项研究将使人们能够更好地理解耐药性和TGF-ß信号传导，这既是癌症治疗的标志物，又是目标。尽管此处确定的机制可能具有了解癌症和定义治疗的一般应用，但我们的研究对临床侵略性，难以治疗的基本样（主要是三阴性）乳腺癌的意义增加了，通常会经历主动的TGF-ß信号传导。这项研究将通过SMAD2/3-介导的miRNA加工来提供对TGF-ß在癌症中的功能转换的新见解。了解TGF-β介导的化学耐药性可能会揭示出新的治疗靶标和策略，从而增强缺乏全身治疗靶标的癌症的化学疗法有效性。我们的长期目标是在初级癌症中验证这种机制，并建立标准方法，以鉴定适合针对TGF-β耐药作用的疗法的患者，并了解TGF-β介导的miRNA在人类癌症中的全球效应。

项目成果

Cancer-derived extracellular vesicles: the 'soil conditioner' in breast cancer metastasis?

• DOI: 10.1007/s10555-016-9639-8
• 发表时间: 2016-12
• 期刊: Cancer metastasis reviews
• 作者: Chin AR;Wang SE
• 通讯作者: Wang SE

Cancer Tills the Premetastatic Field: Mechanistic Basis and Clinical Implications.

• DOI: 10.1158/1078-0432.ccr-16-0028
• 发表时间: 2016-08-01
• 期刊: Clinical cancer research : an official journal of the American Association for Cancer Research
• 作者: Chin AR;Wang SE
• 通讯作者: Wang SE

Macrophage immunomodulation by breast cancer-derived exosomes requires Toll-like receptor 2-mediated activation of NF-κB.

• DOI: 10.1038/srep05750
• 发表时间: 2014-07-18
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Chow A;Zhou W;Liu L;Fong MY;Champer J;Van Haute D;Chin AR;Ren X;Gugiu BG;Meng Z;Huang W;Ngo V;Kortylewski M;Wang SE
• 通讯作者: Wang SE

Cancer-secreted miR-105 destroys vascular endothelial barriers to promote metastasis.

• DOI: 10.1016/j.ccr.2014.03.007
• 发表时间: 2014-04-14
• 期刊: Cancer cell
• 影响因子: 50.3
• 作者: Zhou W;Fong MY;Min Y;Somlo G;Liu L;Palomares MR;Yu Y;Chow A;O'Connor ST;Chin AR;Yen Y;Wang Y;Marcusson EG;Chu P;Wu J;Wu X;Li AX;Li Z;Gao H;Ren X;Boldin MP;Lin PC;Wang SE
• 通讯作者: Wang SE