Tension-Stat3-miR-mediated metastasis

Tension-Stat3-miR介导的转移

• 批准号: 9237209
• 负责人: VICTORIA L. SEEWALDT
• 金额: $ 57.64万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9237209
• 关键词: Ablation; African American; Aggressive behavior; Atypia; Atypical hyperplasia; Automobile Driving; BRCA1 Mutation; Biological Markers; Biopsy; Breast Epithelial Cells; Cell Proliferation; Chronic; Clinical; Collagen; Data; Development; Diffuse; Disease; ERBB2 gene; Early Diagnosis; Epithelial; Epithelium; Exhibits; Extracellular Matrix; Family; Feedback; Fibrosis; Functional disorder; High Risk Woman; Human; IL6 gene; Inflammation; Inflammatory; Integrins; Lesion; Link; Malignant Neoplasms; Mammary Neoplasms; Mammary gland; Mastectomy; Mediating; MicroRNAs; Molecular; Monitor; Mus; Neoplasm Metastasis; Noninfiltrating Intraductal Carcinoma; Nuclear; Pathologic; Pathway interactions; Patients; Phosphoproteins; Pre-Clinical Model; Premalignant; Premenopause; Preneoplastic Change; Prevalence; Prevention strategy; Recording of previous events; Risk; Risk Reduction; Signal Pathway; Signal Transduction; Testing; Time; Tissues; Tumor Biology; Tumor Cell Invasion; Woman; base; breast lesion; cancer initiation; cancer subtypes; cancer therapy; cohort; curative treatments; epithelial to mesenchymal transition; high risk; improved; in vivo; innovation; macrophage; malignant breast neoplasm; molecular pathology; mortality; mouse model; outcome forecast; prevent; public health relevance; response; treatment strategy; triple-negative invasive breast carcinoma; tumor; tumor progression

 DESCRIPTION (provided by applicant): Triple-negative breast cancers (TNBC) exhibit aggressive tumor biology and carry a poor prognosis, particularly in premenopausal African American (AA) women who carry a disproportionate burden of breast cancer mortality. The precursor lesion for TNBC is poorly characterized and the pathophysiology of TNBC is not well understood so therapies often fail to achieve complete pathological response and the disease is frequently non-curative. This proposal aims to clarify the molecular pathology of TNBC so that biomarkers for early diagnosis, prevention strategies and curative therapies can be developed. In our high-risk, multi-institutional cohort, with a high percent of AA women, we found that during breast cancer initiation, pStat3 is high as is ECM stiffness and integrin/YAP mechanosignaling, and miRNAs implicated in tumor progression/aggression. TNBCs had the highest inflammation, pStat3 and miR-18a, the stiffest ECM and the lowest miR-203. Mouse studies indicated preventing inflammation decreases fibrosis and that reducing ECM stiffening lower pStat3 and inflammation and EMT and metastasis. Driving mammary mechanosignaling induced miR-18a and EMT and enhanced tumor aggression/metastasis. This suggests that an activated Stat3/tissue tension feedback loop, linked to tissue inflammation, promotes TNBC by engaging mechanosignaling pathways that alter miRs and induce an EMT and tumor aggression. While some breast cancers arise from focal lesions, TNBCs often appear to arise diffusely. We predict that in women at high-risk for TNBC (familial association, BRCA1 mutation) there is a dynamic and reciprocal relationship between the "at risk epithelium" and tissue tension that activates mechano-signaling pathways and induces Stat3/miRNA to 1) initiate TNBC, 3) induce an EMT and/or enhance tumor aggression, that 3) can be used to idenify precancerous lesions that have a high likelihood of progression to TNBC, and 4) could be used to monitor efficacy of prevention strategies and identify targets to improve TNBC treatment. We will use preclinical models to test: 1) if there is a reciprocal relationship between inflammation, pStat3 and tissue tension that promotes TNBC progression/aggression and 2) if this is mediated through miRs and EMT. We will examine a clinical cohort of high risk women who rapidly develop TNBCs to 3) test the prevalence of this signaling circuit in biopsies from women with TNBC and determine whether these biomarkers can identify precancerous lesions that have a high likelihood of progression to TNBC. Significance: Our studies could transform concepts of breast cancer by demonstrating that tissue tension could molecularly-prime tissue to malignancy. Markers that identify preneoplastic changes in TNBC, that could be used to monitor efficacy of risk reduction strategies, would have a transformative impact on TNBC mortality rates and particularly AA women.

 描述（由适用提供）：三阴性乳腺癌（TNBC）暴露了侵袭性肿瘤生物学，并具有较差的预后，尤其是在绝经前非洲裔美国人（AA）妇女中，这些妇女的乳腺癌死亡率不成比例。 TNBC的前体病变的特征很差，TNBC的病理生理学尚不清楚，因此疗法通常无法实现完全的病理反应，并且该疾病经常非抑制。该建议旨在阐明TNBC的分子病理，以便可以开发出生物标志物，以进行早期诊断，预防策略和治愈疗法。在我们的高风险，多机构的队列中，有很高比例的AA妇女，我们发现 乳腺癌的启动，PSTAT3较高，ECM刚度和整联蛋白/YAP机制进展也很高，并且在肿瘤进展/攻击中植入了miRNA。 TNBC的感染最高，PSTAT3和miR-18a，最僵硬的ECM和最低的miR-203。小鼠的研究表明，防止注射会降低纤维化，并减少ECM加强较低的PSTAT3以及注射以及EMT和转移。驱动乳腺机理信号传导诱导miR-18a和EMT，并增强肿瘤攻击/转移。这表明与组织感染相关的激活的STAT3/组织张力反馈环通过引入改变MIR并诱导EMT和肿瘤侵略性的机制来促进TNBC。虽然某些乳腺癌是由局灶性病变引起的，但TNBC通常似乎弥漫。 We predict that in women at high-risk for TNBC (familial association, BRCA1 mutation) there is a dynamic and reciprocal relationship between the "at risk epithelium" and tissue tension that activates mechano-signaling pathways and induces Stat3/miRNA to 1) initiate TNBC, 3) induce an EMT and/or enhancement tumor aggressive, that 3) can be used to identify precancerous lesions that have a high向TNBC发展的可能性，4）可用于监测预防策略的有效性，并确定靶标以改善TNBC治疗。我们将使用临床前模型进行测试：1）如果炎症，PSTAT3和组织张力之间存在相互关系， 促进TNBC的进展/攻击性，2）如果通过miR和EMT介导的话。我们将检查迅速发展TNBC的高风险女性的临床队列3）测试TNBC女性活检中这种信号传导电路的流行，并确定这些生物标志物是否可以鉴定出具有很可能进展为TNBC的预先癌病变。意义：我们的研究可以通过证明组织张力可以分子组织到恶性肿瘤来改变乳腺癌的概念。可以用来监测降低风险策略效率的TNBC中质塑性变化的标志物将对TNBC死亡率，尤其是AA妇女产生变革性的影响。