Development Project 3

这个项目的主要目的是促进我们对新的膜相关类固醇受体在乳腺癌进展的多个阶段中的影响的理解。孕酮是膜相关类固醇受体的关键调节因子，妇女健康倡议(WHI)随机试验的数据表明，虽然联合使用雌激素和孕激素更年期激素疗法(CHT)会增加乳腺癌的风险，但单独使用雌激素并不会增加乳腺癌的风险，这突显了黄体酮在乳腺癌病因方面的重要性。在随后的许多研究中，李博士和他的同事率先证明，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更显著增加。然而，黄体酮的使用和小叶乳腺癌风险之间的密切关系背后的生物学机制基本上是未知的。 我们基于人群的乳腺癌研究(Porter和Li博士)以及Ashley博士实验室的体外研究证实了MPR和CXCL12及其受体CXCR4在激素调控的生殖途径中的存在和重要性，这些发现使我们假设，膜相关受体和转移趋化因子，如激素调控的CXCL12和CXCR4，都导致了CHT对小叶乳腺癌和导管乳腺癌的风险和生物学影响的差异。 我们计划从一项正在进行的大规模人群研究中，评估细胞膜孕激素和雌激素受体表达的贡献以及与E-P使用和组织亚型相关的下游效应与特征良好的ILC和IDC肿瘤的关系。将评估ILC和IDC肿瘤的一个子集的全基因组基因表达，以识别和表征与孕激素和乳腺癌之间的关系相关的新因素和新途径。这项研究将提供与乳腺癌病因学相关的重要信息，并可能导致确定新的预防和治疗靶点。该项目还将通过提供DASL分析等最先进的分子技术培训，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FHCRC的两位资深科学家(Porter博士和Li博士)将直接为Ashley博士的职业发展做出贡献。

The overarching purpose of this project is to advance our understanding of the 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 (WHI) 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 ILC 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 of the 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.