Tension-Stat3-miR-mediated metastasis

 描述（由申请人提供）：三阴性乳腺癌（TNBC）表现出侵袭性肿瘤生物学，预后不良，特别是在绝经前非裔美国人（AA）女性中，她们的乳腺癌死亡率负担不成比例。TNBC的前驱病变表征不佳，并且TNBC的病理生理学未被很好地理解，因此疗法通常无法实现完全的病理学反应，并且该疾病通常是非治愈性的。该提案旨在阐明TNBC的分子病理学，以便开发用于早期诊断，预防策略和治愈性治疗的生物标志物。在我们的高风险、多机构队列中，AA女性比例很高，我们发现， 在乳腺癌发生中，pStat 3高，ECM硬度和整合素/雅普机械信号传导以及与肿瘤进展/侵袭有关的miRNA也高。TNBC具有最高的炎症、pStat 3和miR-18 a、最硬的ECM和最低的miR-203。小鼠研究表明，预防炎症可减少纤维化，减少ECM硬化可降低pStat 3和炎症以及EMT和转移。驱动乳腺机械信号传导诱导miR-18 a和EMT并增强肿瘤侵袭/转移。这表明与组织炎症相关的活化的Stat 3/组织张力反馈环通过参与改变miR并诱导EMT和肿瘤侵袭的机械信号传导途径来促进TNBC。虽然一些乳腺癌起源于局灶性病变，但TNBC通常表现为弥漫性出现。我们预测，在TNBC高危女性中，（家族关联，BRCA 1突变）在“风险上皮”和组织张力之间存在动态和相互关系，其激活机械信号传导途径并诱导Stat 3/miRNA以1）引发TNBC，3）诱导EMT和/或增强肿瘤侵袭，3）可用于鉴别具有进展为TNBC的高可能性的癌前病变，以及4）可用于监测预防策略的功效并确定改善TNBC治疗的靶标。我们将使用临床前模型来测试：1）炎症、pStat 3和组织张力之间是否存在相互关系， 促进TNBC进展/攻击和2）如果这通过miR和EMT介导。我们将检查快速发展为TNBC的高风险女性的临床队列，以3）测试来自TNBC女性的活组织检查中这种信号传导回路的患病率，并确定这些生物标志物是否可以识别具有进展为TNBC的高可能性的癌前病变。意义：我们的研究可以通过证明组织张力可以在分子上引发组织恶性化来改变乳腺癌的概念。识别TNBC肿瘤前变化的标志物，可用于监测降低风险策略的有效性，将对TNBC死亡率，特别是AA女性产生变革性影响。

 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.