Tension-Stat3-miR-mediated metastasis

 描述(申请人提供)：三阴性乳腺癌(TNBC)表现出侵袭性的肿瘤生物学和预后不良，特别是在绝经前的非裔美国人(AA)妇女，她们承担着不成比例的乳腺癌死亡负担。TNBC的前驱病变特征较差，其病理生理学机制尚不清楚，因此治疗往往不能达到完全的病理应答，而且这种疾病往往是无法治愈的。这项建议旨在阐明TNBC的分子病理学，以便开发用于早期诊断、预防策略和治疗的生物标记物。在我们的高风险、多机构队列中，AA女性的比例很高，我们发现在 在乳腺癌的发生、发展和侵袭过程中，pStat3、ECM刚性和整合素/YAP机制信号转导高表达，miRNAs参与肿瘤的进展/侵袭。TNBCs炎症程度最高，pStat3和miR-18a最强，ECM最硬，miR-203最低。小鼠研究表明，预防炎症可以减少纤维化，减少细胞外基质，降低pStat3和炎症，减少EMT和转移。驱动乳腺机械信号转导诱导miR-18a和EMT，增强肿瘤侵袭/转移。这表明激活的STAT3/组织张力反馈环与组织炎症有关，通过参与改变miR并诱导EMT和肿瘤侵袭的机械信号通路促进TNBC。虽然一些乳腺癌是由局灶性病变引起的，但TNBCs通常似乎是弥漫性的。我们预测，在TNBC(家族性关联，BRCA1突变)的高危女性中，“风险上皮”和组织张力之间存在动态和相互作用的关系，组织张力激活机械信号通路并诱导STAT3/miRNA来1)启动TNBC，3)诱导EMT和/或增强肿瘤侵袭性，3)可以用于识别有很大可能进展为TNBC的癌前病变，以及4)可以用于监测预防策略的有效性和确定改善TNBC治疗的靶点。我们将使用临床前模型来测试：1)炎症、pStat3和组织张力之间是否存在相互作用的关系 促进TNBC进展/攻击性；2)如果这是通过MIR和EMT调节的话。我们将检查一组快速发展为TNBCs的高危女性的临床队列，以3)在患有TNBC的妇女的活检组织中测试这种信号通路的流行率，并确定这些生物标志物是否可以识别有很高可能性进展到TNBC的癌前病变。意义：我们的研究可能会改变乳腺癌的概念，因为我们的研究表明，组织张力可以从分子上启动组织向恶性肿瘤的转化。识别TNBC癌前病变的标志物，可以用来监测降低风险策略的有效性，将对TNBC死亡率，特别是再生障碍性贫血妇女产生革命性影响。

 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.