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

本项目的首要目的是促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。孕激素是膜相关类固醇受体的关键调节剂，并且来自妇女健康倡议（WHl）随机试验的数据强调了孕激素对于乳腺癌病因的重要性，该数据表明，虽然使用联合雌激素和孕激素绝经激素治疗（CHT）增加了乳腺癌的风险，但单独使用雌激素不会。Li博士和他的同事领导了许多后续研究中的第一项，以记录与外源性resistin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更大幅度增加。然而，基本上不知道使用乳腺癌蛋白和小叶乳腺癌风险之间的密切关系的生物学机制。 我们基于人群的乳腺癌研究的结果（Porter和Li博士）以及阿什利博士实验室的体外研究，鉴定了MPR和CXCL 12及其受体CXCR 4在乳腺癌调节的生殖途径中的存在和重要性，使我们假设膜相关受体和转移性化学引诱物，如乳腺癌调节的CXCL 12和CXCR 4，有助于CHT使用对小叶乳腺癌与导管乳腺癌的风险和生物学的不同影响。 我们计划从一项正在进行的大规模人群研究中，评估膜孕激素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。将在ILC和IDC肿瘤的子集中评估全基因组基因表达，以鉴定和表征与孕酮和乳腺癌之间的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（如DASL检测）培训，提高NMSU开展竞争性研究的能力。此外，它还与一名初级科学家合作。瑞安博士阿什利在NMSU，与两名高级FHCRC科学家（博士波特和李）谁将直接有助于博士阿什利的职业发展。

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.