Tissue Tension, RANK and Breast Cancer Risk

乳腺X线摄影密度(MD)和BRCA1基因突变(BRCA1 MT)是乳腺癌的两个重要危险因素。 阐明这些高危女性癌症风险的分子基础并确定生物标记物以识别 将从更密切的监测和化学预防以及验证分子途径中受益的女性 已批准的治疗方法的存在具有重要的临床意义。我们发现体内的细胞外基质(ECM) 患有高MD和BRCA1 MTS的女性更僵硬，僵硬的ECM使乳腺上皮敏感 细胞(MECs)对孕酮诱导更多的受体激活物的核因子kappaB配体(RANKL)。排名刺激 乳腺细胞生长，扩大干细胞，并诱导炎症和乳腺癌转移。我们检测到 MD高的女性乳房中有更多的RANKL，数据表明乳房中的RANKL受体等级更高 患有BRCA1 MTS的女性的组织，她们拥有更多的乳房干细胞，并患上三阴性乳腺癌 (TNBC)。研究还表明，非裔美国人(AA)女性的活动级别可能更高，她们经常发生 TNBCS。因此，我们预测高MD女性患恶性肿瘤的风险是由僵硬的ECM造成的，因为它 使上皮细胞对孕激素敏感，以增加RANK信号，从而驱动乳腺细胞生长和组织 炎症和扩大乳房干细胞频率。这种表型也可以解释为什么倾向于 先前研究表明患有BRCA1 MTS和AA的其他高危女性可能患有TNBCs 更高等级的信令。我们将通过以下方法进行测试：1)在小鼠模型中确定组织力学是否驱动乳腺 增强Rank信号并促进细胞生长和炎症的腺体转化和转移 干细胞扩增。2)探索等级、炎症和干细胞之间的联系和因果关系 来自癌症高危女性和患有TNBCs的女性乳腺组织中的频率和ECM硬度， 而在接受RANKL抑制剂Denosumab治疗的BRCA1 MT妇女的乳房组织中。3)确定如何 细胞外基质僵硬使微血管内皮细胞对孕酮敏感，如果女性的乳房组织有较高的恶性风险 或者TNBCs对黄体酮或RANKL具有内在的敏感性。研究将：1)将RANK信令识别为 乳腺癌风险和TNBCs的生物标记物，并将提供证据支持使用 RANKL抑制剂。3)为MD增加的风险提供生物学基础，4)阐明机制 因此，BRCA1 MTS增加了乳腺癌的发病率，并提供了生物标志物来对这一人群的风险进行分层。5)获得 AA女性侵袭性TNBC乳腺癌的生物学基础。

Mammographic density (MD) and mutations in BRCA1 (BRCA1 MT) are two strong risk factors for breast cancer. Clarifying the molecular basis of the cancer risk in these highrisk women and identifying biomarkers to identify women who would benefit from closer surveillance and chemoprevention, and validating molecular pathways towards which approved therapies exist is clinically important. We found that the extracellular matrix (ECM) in women with high MD and those with BRCA1 MTs is stiffer and that a stiff ECM sensitizes mammary epithelial cells (MECs) to progesterone to induce more receptor activator of NF kappa B ligand (RANKL). RANK stimulates breast cell growth, expands stem cells, and induces inflammation and breast cancer metastasis. We detected more RANKL in the breasts of women with high MD, and data suggest RANK receptors are higher in breast tissue from women with BRCA1 MTs who have more breast stem cells and develop triple negative breast cancer (TNBC). Studies also suggest RANK activity may be higher in African American (AA) women who often develop TNBCs. Thus, we predict that risk to malignancy in women with high MD is fostered by a stiff ECM because it sensitives the epithelium to progesterone to increase RANK signaling that drives breast cell growth and tissue inflammation and expands breast stem cell frequency. This phenotype could also explain the predilection to develop TNBCs in other high-risk women with BRCA1 MTs and AA women who prior studies suggest may have higher RANK signaling. We will test this by: 1) Determining in mouse models if tissue mechanics drives mammary gland transformation and metastasis by enhancing Rank signaling and driving cell growth and inflammation and stem cell expansion. 2) Exploring associations and causality between Rank, inflammation and stem cell frequency and ECM stiffness in breast tissue from women at high risk for cancer and those who develop TNBCs, and in breast tissue from BRCA1 MT women treated with the RANKL inhibitor Denosumab. 3) Determining how ECM stiffness sensitives MECs to progesterone, and if the breast tissue in women at higher risk to malignancy or TNBCs are intrinsically sensitive to progesterone or RANKL. The studies will: 1) Identify RANK signaling as a biomarker for breast cancer risk and TNBCs and will provide evidence to support chemoprevention trials using RANKL inhibitors. 3) Provide a biological basis for the increased risk conferred by MD, 4) Clarify mechanisms whereby BRCA1 MTs increase breast cancer and provide biomarkers to stratify risk in this population. 5) Obtain insight into the biological basis of the aggressive TNBC breast cancers in AA women.