The role of TAZ in breast cancer initiation and progression

TAZ 在乳腺癌发生和进展中的作用

• 批准号: 10192672
• 负责人: Jianmin Zhang
• 金额: $ 39.7万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10192672
• 关键词: Aftercare; Bar Codes; Basal Cell; Binding; Binding Sites; Breast Cancer Cell; Breast Cancer Patient; Breast cancer metastasis; Cancer Relapse; Cell Cycle; Cells; Cessation of life; Clinic; DNA; Data; Disease; E2F transcription factors; Early treatment; Fill-It; Gene Mutation; Genes; Goals; Histopathologic Grade; In Vitro; In complete remission; Incidence; Libraries; Mammary Neoplasms; Mammary gland; Mediating; Messenger RNA; Modeling; Molecular; Morbidity - disease rate; Nature; Neoadjuvant Study; Neoplasm Metastasis; Outcome; Outcome Study; Pathologic; Patients; Population; Pre-Clinical Model; Primary Neoplasm; Prognosis; Property; Proteins; Recurrence; Regulation; Relapse; Reporting; Research; Residual Tumors; Role; Signal Pathway; System; Technology; Testing; Therapeutic; Tissue Microarray; Transcription Coactivator; Transgenic Mice; Translations; Woman; Work; base; breast cancer diagnosis; breast cancer progression; breast cancer survival; breast tumorigenesis; cancer initiation; cancer stem cell; cancer therapy; cancer type; chemotherapy; genome-wide; high risk; improved; in vivo; innovation; knock-down; malignant breast neoplasm; mammary; mouse model; next generation sequencing; novel; oncogene addiction; overexpression; relapse risk; stem cells; targeted agent; therapeutically effective; trait; treatment response; triple-negative invasive breast carcinoma; tumor; tumor heterogeneity; tumor progression

About 10-20% of breast cancers are triple-negative breast cancers (TNBC) that have poorer outcomes and higher risk of recurrence compared to other breast cancer types. It is known that the mRNA and protein levels of TAZ (transcriptional co-activator with PDZ-binding motif) are preferentially higher in TNBC than in other breast cancer (BC) subclasses. Activation of TAZ has been correlated with high histological grade, conferral of breast cancer stem cell (CSC) traits, enhanced tumor metastasis, and poor outcome in BC patients. There is a fundamental gap in understanding how activation of TAZ contributes to tumor relapse and metastasis in TNBC patients. The continued existence of this gap represents an important problem because, until it is filled, it will be impossible to devise rational therapeutic approaches to help improve breast cancer patient survival. The long-term goal is to reduce morbidity in TNBC patients and help improve breast cancer patient survival. The overall objective of this application is to understand the molecular mechanisms by which TAZ initiates breast tumor progression and metastasis. The central hypothesis is that both TAZ-initiated promotion of cell cycle activity and expansion of transformed mammary stem cell (Ma-SC) populations are required for TAZ-initiated breast tumorigenesis. Our hypothesis has been formulated on the basis of our own preliminary data. The rationale for the proposed research is that once it is known how activation of TAZ initiates TNBC progression and metastasis, it will be possible to develop new and innovative approaches for treating TNBCs. To this end, we propose the following aims: (1) identify the critical downstream targets that are required for TAZ to initiate breast cancer progression; (2) determine how TAZ induces the formation of heterogeneous mammary tumors using a unique TAZ transgenic mouse model; and (3) determine the role of TAZ in breast tumor heterogeneity and its impact on tumor metastasis. As the outcome of this study, we expect to identify the critical targets of TAZ that are responsible for TAZ-initiated breast tumor progression and metastasis as well as to establish a well-characterized TAZ transgenic mouse model. Such results are expected to vertically advance our understanding of how TAZ activation contributes to TNBC relapse.

大约10-20%的乳腺癌是三阴性乳腺癌（TNBC），其结果较差， 与其他类型的乳腺癌相比，复发风险更高。已知mRNA和蛋白质水平 TAZ（具有PDZ结合基序的转录共激活因子）的表达在TNBC中优先高于其他TNBC。 乳腺癌（BC）亚类。TAZ的激活与高组织学分级、肿瘤的发生、肿瘤的转移和肿瘤的转移有关。 乳腺癌干细胞（CSC）性状，增强的肿瘤转移，以及BC患者的不良结局。有一个 在理解TAZ激活如何促进TNBC中的肿瘤复发和转移方面存在根本性差距 患者这一差距的继续存在是一个重要的问题，因为在填补这一差距之前， 不可能设计出合理的治疗方法来帮助提高乳腺癌患者的生存率。的 长期目标是降低TNBC患者的发病率，并帮助提高乳腺癌患者的生存率。的 本申请的总体目标是了解TAZ启动乳腺癌的分子机制， 肿瘤进展和转移。中心假设是TAZ启动的细胞周期促进 转化的乳腺干细胞（Ma-SC）群体的活性和扩增是TAZ启动的 乳腺肿瘤发生我们的假设是根据我们自己的初步资料提出的。的 提出的研究的基本原理是，一旦知道TAZ的激活如何启动TNBC进展， 和转移，将有可能开发用于治疗TNBC的新的和创新的方法。为此目的， 我们提出了以下目标：（1）确定技术援助区启动所需的关键下游目标 乳腺癌进展;（2）确定TAZ如何诱导异质性乳腺肿瘤的形成 使用独特的TAZ转基因小鼠模型;和（3）确定TAZ在乳腺肿瘤异质性中的作用 及其对肿瘤转移的影响。作为这项研究的结果，我们希望确定的关键目标， TAZ启动的乳腺肿瘤进展和转移的原因，以及建立 TAZ转基因小鼠模型。这些结果预计将垂直推进我们的 了解TAZ激活如何有助于TNBC复发。

项目成果

Identification of TAZ-Dependent Breast Cancer Vulnerabilities Using a Chemical Genomics Screening Approach.

• DOI: 10.3389/fcell.2021.673374
• 发表时间: 2021
• 期刊: Frontiers in cell and developmental biology
• 影响因子: 5.5
• 作者: Shen H;Chen Y;Wan Y;Liu T;Wang J;Zhang Y;Wei L;Hu Q;Xu B;Chernov M;Frangou C;Zhang J
• 通讯作者: Zhang J