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（申请人提供）：许多化疗药物通过损伤DNA来对抗癌细胞。化疗耐药是癌症治疗的主要临床障碍。癌症患者的化疗耐药机制尚不完全清楚，因此迫切需要化疗药物。确定控制药物反应的因素并开发新疗法以增强治疗效果 转化生长因子（TGF）β（正常细胞中的一种肿瘤抑制因子）在癌症中被劫持以促进疾病进展。 TGF-β 与不良临床结果和化疗耐药性相关，但我们之前的研究表明，在乳腺癌细胞中，TGF-β 会诱导靶向 DNA 损伤传感器 ATM 和 miR-181 的 microRNA（miR-21 和 miR-181）。 MSH2，因此可能调节癌症对基因毒性化疗的反应本研究的目标是剖析其分子机制。 TGF-β 介导的化疗耐药性，并探索增强药物疗效的潜在疗法。在目标 1 中，TGF-β 对细胞对各种 DNA 损伤治疗和抑制聚（ADP-核糖）聚合酶（PARP）的反应的作用。使用已建立的分子和细胞生物学测定法确定了具有不同 p53 状态的乳腺癌细胞的作用。 TGF-β 调节的 miRNA 和 ATM/MSH2 通路将使用基因敲低和过表达策略来确定。在目标 2 中，假设增强 SMAD2/3 与其 RNA 靶标的结合介导癌细胞中 TGF-β 向诱导 miRNA 的功能转变。将检查表达不同水平的 SMAD2/3 辅助因子（即 SMAD4、Drosha 和 p68）的乳腺癌细胞。在目标 3 中，将在动物肿瘤模型中评估 TGF-β 对化疗反应的影响以及前两个目标中确定的机制。将探索治疗性抑制 TGF-β 功能并增强治疗效果，尽管本文确定的机制可能具有一定的局限性，但这项研究将有助于更好地理解耐药性和 TGF-β 信号传导作为癌症治疗的标记物和靶标。一般应用到通过了解癌症并确定治疗方法，我们的研究对于经常经历活跃 TGF-β 信号传导的临床侵袭性、难以治疗的基底细胞样（主要是三阴性）乳腺癌具有重要意义。这项研究将为功能开关提供新的见解。通过 SMAD2/3 介导的 miRNA 加工来了解 TGF-β 在癌症中的作用，了解 TGF-β 介导的化疗耐药性可能会揭示新的治疗靶点和策略，从而增强缺乏全身治疗靶点的癌症的化疗效果。验证原发性癌症中的这一机制，并建立标准方法来识别适合针对 TGF-β 耐药作用的治疗的患者，并了解 TGF-β 介导的 miRNA 失调在人类癌症中的整体影响。

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