Tissue Tension, RANK and Breast Cancer Risk

组织张力、RANK 和乳腺癌风险

基本信息

批准号：
9918875
负责人：
E.Shelley Hwang
金额：
$ 57.09万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-02-09 至 2023-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9918875
关键词：
African American Aggressive behavior Automobile Driving BRCA1 Mutation BRCA1 gene Biological Biological Markers Breast Breast Cancer Patient Breast Cancer Risk Factor Breast Epithelial Cells Breast cancer metastasis Cancer Biology Cells Chemoprevention Clinical Clinical Trials Data Dose Epithelial Epithelium Etiology Experimental Models Extracellular Matrix Fostering Frequencies High Risk Woman High-Risk Cancer Human Image Incidence Inflammation Ligands Link Malignant Neoplasms Mammaplasty Mammary Gland Parenchyma Mammary Neoplasms Mammary gland Mammographic Density Mechanics Methods Molecular Mus Mutation Neoplasm Metastasis Organoids Pathway interactions Patients Phenotype Population Populations at Risk Prevention Prevention strategy Progesterone Risk Risk Factors Role Signal Transduction Supplementation Techniques Testing Tissue Model Tissues Transgenic Organisms Tumor Tissue Woman cancer risk cell growth high risk high risk population inhibitor/antagonist insight malignant breast neoplasm mouse model neoplastic cell pre-clinical prophylactic mastectomy receptor receptor activator of NF-kappa B stem stem cells surveillance strategy triple-negative invasive breast carcinoma tumor

项目摘要

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.

BRCA1（BRCA1 MT）的乳房X线摄影密度（MD）和突变是乳腺癌的两个强大危险因素。阐明这些高速妇女中癌症风险的分子基础，并确定生物标志物以识别将受益于更仔细的监视和化学预防，并验证分子途径的妇女存在批准的疗法在临床上很重要。我们发现细胞外基质（ECM） MD高的女性和患有BRCA1 MTS的女性僵硬，ECM僵硬地使乳腺上皮敏感细胞（MEC）到孕酮，诱导更多NF Kappa B配体（RANKL）的受体激活剂。等级刺激乳腺细胞的生长，扩展干细胞并诱导炎症和乳腺癌转移。我们检测到 MD高女性的乳房中有更多的RANKL，数据表明等级受体在乳房中更高 BRCA1 MT的女性的组织，乳腺干细胞更多并发展出三重阴性乳腺癌（TNBC）。研究还表明，在经常发展的非裔美国人（AA）妇女中，排名活动可能更高 TNBC。因此，我们预测，高MD女性恶性肿瘤的风险由僵硬的ECM促进对孕酮的上皮敏感，以增加驱动乳房细胞生长和组织的等级信号传导炎症并扩大乳房干细胞的频率。这种表型也可以解释先前研究表明可能有BRCA1 MTS和AA女性的其他高危女性中的TNBC 较高的等级信号传导。我们将通过：1）在小鼠模型中确定组织力学是否驱动乳腺腺体转化和转移通过增强等级信号传导和驱动细胞的生长以及炎症以及干细胞膨胀。 2）探索等级，炎症和干细胞之间的关联和因果关系来自癌症高风险的乳房组织中的频率和ECM僵硬，以及患有TNBC的患者，在用RANKL抑制剂Denosumab治疗的BRCA1 MT女性的乳房组织中。 3）确定如何 ECM刚度对孕酮的敏感性以及女性的乳房组织是否具有更高的恶性肿瘤或TNBC对孕酮或RANKL本质上敏感。研究将：1）确定等级信号作为一个乳腺癌风险和TNBC的生物标志物，将提供证据，以支持使用化学预防试验 RANKL抑制剂。 3）为MD赋予的风险增加提供生物学基础，4）澄清机制因此，BRCA1 MTS增加了乳腺癌并提供生物标志物来分层该人群的风险。 5）获得深入了解AA女性侵略性TNBC乳腺癌的生物学基础。