Mechanisms underlying pro-metastatic effects of estrogen in the brain niche

项目摘要 虽然已经确定雌二醇（E2）--绝经前的主要卵巢激素--具有促有丝分裂作用， 雌激素受体阳性（ER+）乳腺癌的作用，新的证据表明，E2促进 ER阴性（ER-）肿瘤的肿瘤发生和转移通过对微环境的影响。E2游戏 众所周知，成年人大脑中的神经营养和神经保护功能是通过调节 神经营养因子，生长因子和趋化因子，然而，如何E2促进脑转移进展 仍然不明确。这一提议的科学前提是，E2通过以下方式促进脑转移： 调节脑微环境中的ER+细胞。我们的长期目标是确定 E2在脑中的促转移作用的基础，以确定预防或治疗脑转移的新策略。 转移我们的研究表明，E2通过调节ER+促进实验性脑转移 反应性星形胶质细胞，其在脑转移定植期间早期被诱导，并且对于脑转移至关重要。 转移性进展脑转移瘤周围的反应性星形胶质细胞表达ER基因（ERα和ER β）， ERβ），并响应于E2，上调神经营养因子（BDNF）和生长因子（EGF），激活前 转移途径（TRKB、EGFR、HER 2）。E2还抑制趋化因子（Ccl 2，Ccl 3，Ccl 4， Ccl 5），其促进小胶质细胞的募集和极化成M1肿瘤抑制表型。我们 中心假设是E2通过至少两种独立的机制促进脑转移：1） BDNF的上调导致转移性癌细胞中TRKB/EGFR信号传导的活化，和2） 在早期脑转移灶中抑制肿瘤抑制性M1小胶质细胞。因此，针对 芳香酶、E2/ER信号传导或下游BDNF/TRKB/EGFR活化可用于预防或治疗 脑转移在目标1中，我们将确定E2如何在转移性小生境中上调BDNF，以及是否 TRKB/EGFR/HER 2的BDNF激活是响应于E2的脑转移增加的机制。在 目的2我们将确定E2如何调节小胶质细胞的激活和极化在大脑的早期阶段 转移，以及这是否是E2引起脑转移增加的机制。在目标3中， 将确定靶向E2/ER信号传导或下游BDNF/TRKB/EGFR活化是否减少脑 转移定植和体内进展。这一贡献将是重要的，因为定义 E2调节大脑生态位的机制可以为预防和治疗 高危女性脑转移。这一建议是创新的，因为它代表了一种新的模式， 考虑E2和癌症中的大脑生态位;它将通过定义E2如何调节小胶质细胞来填补关键空白 它将确定芳香酶抑制剂和/或ANA-12是否在脑转移中具有临床前功效。 TrkB+脑转移瘤的预防和治疗。

PROJECT SUMMARY While it is well established that estradiol (E2) -the main premenopausal ovarian hormone-, plays mitogenic roles in estrogen-receptor positive (ER+) breast cancer, emerging evidence shows that E2 promotes tumorigenesis and metastases of ER negative (ER-) tumors through effects on the microenvironment. E2 plays well known neurotrophic and neuroprotective functions in the adult brain by regulating the expression of neurotrophins, growth factors and chemokines, however, how E2 promotes brain metastatic progression remains ill-defined. The scientific premise of this proposal is that E2 promotes brain metastasis by modulating ER+ cells in the brain microenvironment. Our long-term goal is to define the mechanisms underlying the pro-metastatic effects of E2 in the brain to identify novel strategies to prevent or treat brain metastases. Our studies have shown that E2 promotes experimental brain metastases by modulating ER+ reactive astrocytes, which are induced early during brain metastatic colonization and are essential for brain metastatic progression. Reactive astrocytes surrounding brain metastases express both ER genes (ERα and ERβ), and in response to E2, upregulate neurotrophins (BDNF) and growth factors (EGF) that activate pro- metastatic pathways (TRKB, EGFR, HER2) in cancer cells. E2 also represses chemokines (Ccl2, Ccl3, Ccl4, Ccl5), which promote recruitment and polarization of microglia into an M1 tumor-suppressive phenotype. Our central hypothesis is that E2 promotes brain metastases by at least two independent mechanisms: 1) upregulation of BDNF leading to activation of TRKB/EGFR signaling in metastatic cancer cells, and 2) repression of tumor-suppressive M1 microglia in the early brain metastatic niche. Therefore, targeting aromatase, E2/ER signaling or downstream BDNF/TRKB/EGFR activation can be used to prevent or treat brain metastases. In Aim 1 we will determine how E2 upregulates BDNF in the metastatic niche, and whether BDNF activation of TRKB/EGFR/HER2 is a mechanism of increased brain metastases in response to E2. In Aim 2 we will determine how E2 regulates microglia activation and polarization at early stages of brain metastases, and whether this is a mechanism of increased brain metastases in response to E2. In Aim 3 we will determine whether targeting E2/ER signaling or downstream BDNF/TRKB/EGFR activation reduces brain metastatic colonization and progression in vivo. This contribution will be significant because defining the mechanisms by which E2 modulates the brain niche could provide alternatives for prevention and treatment of brain metastases in women at high risk. This proposal is innovative because it represents a new paradigm in thinking about E2 and the brain niche in cancer; it will fill a critical gap by defining how E2 modulates microglia during brain metastasis and, it will define if aromatase inhibitors and/or ANA-12 have preclinical efficacy in prevention and treatment of TrkB+ brain metastases.