Hormonal regulation of the brain microenvironment and its contribution to brain m

描述（由申请人提供）：候选人是一名博士后研究员，在科罗拉多大学安舒茨医学院（AMC，赞助机构）过渡到研究助理教授。她的目标是建立和指导一个由校外资助的实验室， 大学水平的研究机构，最直接的是，在未来3年内过渡到一个完全独立的位置。她的背景，研究经验和出版物的记录表明她致力于癌症研究的职业生涯，她适合进行这些研究，以及她进行创新和高度转化研究的能力。职业发展计划和拟议研究旨在为候选人提供独立开展研究所需的技能、经验和工资支持，以检查CNS转移性疾病激素调节的潜在机制。该计划将巩固候选人的专业知识，并产生高影响力的出版物和初步数据，以竞争R 01资金。候选人的价值在于她的导师和合作者团队的大力支持，以及对她职业发展的坚定机构承诺。候选人的机构是一个NCI指定的癌症中心，拥有杰出的乳腺癌研究小组和设备齐全的设施。研究环境是最佳的，以支持研究计划和候选人的职业生涯。研究计划：脑转移是癌症患者的一个重大医疗问题。10 - 16%的转移性乳腺癌患者出现症状性脑转移，约80%的患者在诊断后一年内死亡。由于乳腺癌脑转移灶中雌激素受体（ER）表达缺失，导致对激素信号在乳腺癌脑转移灶进展中作用的研究被忽视。原发性和转移性ER-乳腺癌不用抗雌激素疗法治疗，因为它假定它们是无效的。然而，初步数据显示，17-？雌二醇（E2）通过星形胶质细胞诱导EGFR配体的上调，星形胶质细胞是围绕和浸润脑转移的细胞。此外，脑转移瘤细胞系显示出响应于E2处理的星形胶质细胞的迁移和增殖增加。由于EGFR在脑转移性乳腺肿瘤中过表达，并且其活化是已知的侵袭、迁移和转移的驱动因素，因此假设这是E2诱导的旁分泌信号传导有助于ER-乳腺癌的脑转移能力的机制之一。由性腺或肾上腺产生的类固醇激素穿过血脑屏障，并且也由神经元和星形胶质细胞中表达的芳香化酶局部产生。重要的是，用于治疗ER+肿瘤的芳香酶抑制剂和抗雌激素可以穿过血脑屏障，并且由于其对脑微环境的影响，可用于治疗所有转移性脑肿瘤。该提案将测试新的假设，即雌激素介导的脑微环境的反应，特别是星形胶质细胞介导的，有助于转移进展独立于肿瘤ER状态，抗雌激素治疗将有效地治疗脑转移瘤。目的1将验证E2激活星形胶质细胞中基因组ER依赖性反应，导致影响脑转移的生长因子分泌的假设。目的2将阐明雌激素刺激的星形胶质细胞增加脑转移性乳腺癌侵袭、迁移和增殖的机制。目的3将检验E2促进脑转移的假设 ER-乳腺癌细胞在体内的定植。

DESCRIPTION (provided by applicant): The Candidate is a postdoctoral fellow transitioning to Assistant professor of Research at University of Colorado Anschutz Medical Campus (AMC, sponsoring institution). Her goal is to establish and direct an extramurally funded laboratory at a University level research institution and most immediately, to transition to a fully independent position in the next 3 years. Her background, research experience and record of publications demonstrate her commitment to a career in cancer research, her suitability to conduct these studies, and her ability to conduct innovative and highly translational research. The career development plan and proposed studies were designed to provide the candidate with the skills, experiences and salary support necessary to independently perform research studies examining the underlying mechanisms of hormonal regulation of metastatic disease in the CNS. This plan will consolidate the candidate's expertise and produce high impact publications and preliminary data to be competitive for R01 funding. The candidate counts with strong support from her mentors and team of collaborators, as well as strong institutional commitment to her career development. The candidate's institution is a NCI-designated Cancer Center with an outstanding breast cancer research group and exceptionally equipped facilities. The research environment is optimal to support both the research plan and the candidate's career. Research plan: Brain metastases represent a substantial health care problem in cancer patients. Ten to 16% of patients with metastatic breast cancer develop symptomatic brain metastases and ~80% die within one year of diagnosis. The absence of estrogen receptor (ER) expression in breast tumors that frequently metastasize to the brain has led to the neglect of studies on the role of hormone signaling in the progression of breast cancer brain metastasis. Primary and metastatic ER- breast cancers are not treated with anti-estrogen therapies since it assumed they are ineffective. However, preliminary data shows that 17-?-estradiol (E2) induces upregulation of EGFR ligands by astrocytes, cells that surround and infiltrate brain metastasis. Furthermore, brain metastatic cell lines show increased migration and proliferation in response to E2-treated astrocytes. Since EGFR is overexpressed in brain metastatic breast tumors and its activation is a known driver of invasion, migration and metastasis, it is hypothesized this is one of the mechanisms by which E2-induced paracrine signaling contributes to the brain metastatic ability of ER- breast cancers. Steroid hormones produced by gonads or adrenals cross the blood brain barrier, and are also produced locally by aromatase expressed in neurons and astrocytes. Importantly, aromatase inhibitors and anti-estrogens used for the treatment of ER+ tumors can cross the blood brain barrier and could be useful for treatment of all metastatic brain tumors because of their effects on the brain microenvironment. This proposal will test the novel hypothesis that estrogen-mediated responses of the brain microenvironment, particularly mediated by astrocytes, contributes to metastases progression independently of tumor ER status, and that anti-estrogen therapies will effectively treat brain metastases. Aim 1 will test te hypothesis that E2 activates genomic ER- dependent responses in astrocytes, leading to the secretion of growth factors that affect brain metastases. Aim 2 will elucidate the mechanism(s) by which estrogen-stimulated astrocytes increase brain-metastatic breast cancer invasion, migration and proliferation. Aim 3 will test the hypothesis that E2 contributes to brain metastatic colonization by ER- breast cancer cells in vivo.