Tissue Tension, RANK and Breast Cancer Risk

乳房 X 光密度 (MD) 和 BRCA1 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，并确定生物标志物来识别 受益于更密切监测和化学预防以及分子途径验证的女性 已批准的治疗方法的存在具有临床重要意义。我们发现细胞外基质（ECM） 具有高 MD 和 BRCA1 MT 的女性更僵硬，僵硬的 ECM 会使乳腺上皮敏感 细胞 (MEC) 与黄体酮结合以诱导更多的 NF kappa B 配体 (RANKL) 受体激活剂。 RANK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 高 MD 女性乳房中的 RANKL 较多，数据表明乳房中的 RANK 受体较高 来自携带 BRCA1 MT 的女性的组织，她们有更多的乳腺干细胞并患上三阴性乳腺癌 （TNBC）。研究还表明，经常发展的非洲裔美国 (AA) 女性的 RANK 活性可能更高 TNBC。因此，我们预测，僵硬的 ECM 会增加患有高 MD 的女性的恶性肿瘤风险，因为它 使上皮细胞对孕酮敏感，增加 RANK 信号传导，促进乳腺细胞生长和组织 炎症并增加乳腺干细胞频率。这种表型也可以解释对 在其他患有 BRCA1 MT 的高危女性和先前研究表明可能患有 AA 的女性中发生 TNBC 更高的 RANK 信号。我们将通过以下方式对此进行测试：1）在小鼠模型中确定组织力学是否驱动乳腺 通过增强 Rank 信号传导并驱动细胞生长和炎症来实现腺体转化和转移， 干细胞扩增。 2) 探索Rank、炎症和干细胞之间的关联和因果关系 癌症高危女性和 TNBC 患者的乳腺组织中的频率和 ECM 硬度， 以及接受 RANKL 抑制剂 Denosumab 治疗的 BRCA1 MT 女性的乳腺组织。 3）确定如何 ECM 僵硬使 MEC 对黄体酮敏感，如果女性的乳腺组织发生恶性肿瘤的风险更高 或 TNBC 本质上对孕酮或 RANKL 敏感。这些研究将： 1) 将 RANK 信号确定为 乳腺癌风险和 TNBC 的生物标志物，并将提供证据支持使用 RANKL 抑制剂。 3) 为 MD 带来的风险增加提供生物学基础，4) 阐明机制 BRCA1 MT 会增加乳腺癌发病率，并提供生物标志物来分层该人群的风险。 5) 获取 深入了解 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.