Full Project 3: Advancing Understanding of Hormonal Contributors to Breast Cance

完整项目 3：增进对乳腺癌激素贡献者的了解

• 批准号: 8641897
• 负责人: Ryan Lynn Ashley
• 金额: $ 8.66万
• 依托单位: NEW MEXICO STATE UNIVERSITY LAS CRUCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8641897
• 关键词: Arts; Biological; Biological Assay; Biology; Breast; CXCL12 gene; CXCR4 Receptors; CXCR4 gene; Cancer Etiology; Chemotactic Factors; Data; Ductal; Estrogen Receptors; Estrogens; Gene Expression; Genome; Histologic; Hormonal; Hormones; In Vitro; Laboratories; Lead; Lobular; Membrane; Menopause; Molecular; Pathway interactions; Phase; Prevention; Progesterone; Progesterone Receptors; Progestins; Research; Risk; Scientist; Steroid Receptors; Techniques; Training; Women' s Health; anticancer research; cancer risk; career development; hormone therapy; malignant breast neoplasm; novel; population based; randomized trial; receptor; receptor expression; reproductive; therapeutic target; tumor; tumor progression

The overarching purpose of this project is to advance our understanding ofthe influence of novel membrane associated steroid receptors on multiple phases of breast cancer progression. Progesterone is a key regulator of the membrane-associated steroid receptors and the importance of progesterone with respect to breast cancer etiology is highlighted by data from the Women's Health Initiative (WHl) randomized trials indicating that while use of combined estrogen and progestin menopausal hormone therapy (CHT) increases risk of breast cancer, use of estrogen alone does not. Dr. Li and his colleagues led the first of many subsequent studies to document that the risk of breast cancer associated with exogenous progestin use is primarily restricted to a more substantial increase in the risk of breast cancers of a lobular histologic type. However, the biological mechanisms underlying the strong relationship between progestin use and lobular breast cancer risk are essentially unknown. The findings from our population-based breast cancer studies (Drs. Porter and Li) and from in vitro studies in Dr. Ashley's laboratory identifying the presence and importance ofthe MPRs and CXCL12 and its receptor, CXCR4 in hormone-regulated reproductive pathways, lead us to hypothesize that both membrane associated receptors and metastatic chemoattractants, such as hormone-regulated CXCL12 and CXCR4, contribute to the differential impact of CHT use on risks and biology of lobular vs. ductal breast cancer. We plan to evaluate the contribution of membrane progesterone and estrogen receptor expression and downstream effects in relation to E+P use and histological subtype in well characterized ILC and IDC tumors from a large ongoing population-based study. Whole genome gene expression will be assessed in a subset of the lLC and IDC tumors to identify and characterize new factors and pathways relevant to the relationship between progesterone and breast cancer. This study will provide vital information relevant to breast cancer etiology and could lead to the identification of novel prevention and therapeutic targets. This project will also increase the capacity of NMSU to conduct competitive research through providing training on state ofthe art molecular techniques such as the DASL assay. Additionally, it partners a junior scientist. Dr. Ryan Ashley at NMSU, with two senior FHCRC scientists (Drs. Porter and Li) who will contribute directly to Dr. Ashley's career development.

该项目的首要目的是增进我们对新型膜相关类固醇受体对乳腺癌进展多个阶段的影响的理解。黄体酮是膜相关类固醇受体的关键调节剂，女性健康倡议 (WHl) 随机试验的数据强调了黄体酮在乳腺癌病因学方面的重要性，该试验表明，在使用雌激素和孕激素联合治疗的更年期激素疗法（ CHT）会增加患乳腺癌的风险，而单独使用雌激素则不会。李博士和他的同事领导了许多后续研究中的第一项，证明与外源性孕激素使用相关的乳腺癌风险主要限于小叶组织学类型乳腺癌风险的大幅增加。然而，孕激素的使用与小叶乳腺癌风险之间存在密切关系的生物学机制基本上尚不清楚。 我们基于人群的乳腺癌研究（Porter 博士和 Li 博士）以及 Ashley 博士实验室的体外研究的结果确定了 MPR 和 CXCL12 及其受体 CXCR4 在激素调节的生殖途径中的存在和重要性，引导我们假设膜相关受体和转移化学引诱剂，例如激素调节的 CXCL12 和 CXCR4，有助于 CHT 使用对癌症风险和生物学的不同影响小叶乳腺癌与导管乳腺癌。 我们计划通过一项正在进行的大型基于人群的研究，评估膜孕酮和雌激素受体表达的贡献以及与 E+P 使用和组织学亚型相关的下游效应，以充分表征 ILC 和 IDC 肿瘤。将在 lLC 和 IDC 肿瘤的子集中评估全基因组基因表达，以识别和表征与孕酮和乳腺癌之间关系相关的新因素和途径。这项研究将提供与乳腺癌病因学相关的重要信息，并可能导致新的预防和治疗靶点的确定。该项目还将通过提供最先进的分子技术（例如 DASL 测定）培训来提高 NMSU 进行竞争性研究的能力。此外，它还与一名初级科学家合作。 NMSU 的 Ryan Ashley 博士和两位 FHCRC 资深科学家（Porter 博士和 Li 博士）将直接为 Ashley 博士的职业发展做出贡献。