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

项目总结 虽然众所周知，绝经前的主要卵巢激素--雌二醇(E_2)--具有促分裂作用 在雌激素受体阳性(ER)乳腺癌中的作用，新的证据表明E2促进 ER阴性肿瘤的发生和转移通过对微环境的影响。E2播放 众所周知，成人脑中的神经营养和神经保护功能是通过调节 然而，神经营养因子、生长因子和趋化因子是如何促进脑转移进展的 仍然没有明确的定义。这一提议的科学前提是，E2通过以下方式促进脑转移 调节大脑微环境中的内质网细胞。我们的长期目标是定义这些机制 研究E2在大脑中促进肿瘤转移的作用，以确定预防或治疗大脑的新策略 转移瘤。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，在脑转移定植过程中早期诱导，对大脑至关重要 转移的进展。脑转移瘤周围的反应性星形胶质细胞表达ER基因(ERα和ER ERβ)，并且作为对E2的响应，上调神经营养因子和生长因子，从而激活前 癌细胞中的转移途径(TrkB、EGFR、HER2)。E2还抑制趋化因子(CCL2、CCl3、CCl4、 CCL5)，促进小胶质细胞的募集和极化为M1肿瘤抑制表型。我们的 中心假说是，E2至少通过两种独立的机制促进脑转移：1) BDNF上调导致转移癌细胞中TrkB/EGFR信号的激活，以及2) 肿瘤抑制型M1小胶质细胞在早期脑转移灶中的抑制作用。因此，目标是 芳香酶、E2/ER信号或下游BDNF/TrkB/EGFR的激活可用于预防或治疗 脑转移瘤。在目标1中，我们将确定E2如何上调转移的利基中的BDNF，以及是否 BDNF激活TrkB/EGFR/HER2是E2增加脑转移的机制之一。在……里面 目的2我们将确定雌激素如何在大脑早期阶段调节小胶质细胞的激活和极化 转移，以及这是否是E2导致脑转移增加的机制。在《目标3》中我们 将决定靶向E2/ER信号或下游BDNF/TrkB/EGFR激活是否会减少大脑 体内的转移性定植和进展。这一贡献将是重大的，因为定义 雌激素调节脑微生态位的机制可能为预防和治疗高血压提供替代方案 高危女性的脑转移。这一建议具有创新性，因为它代表了 思考E2和癌症中的大脑利基；它将通过定义E2如何调节小胶质细胞来填补一个关键的空白 在脑转移过程中，它将定义芳香酶抑制剂和/或ANA-12是否具有临床前疗效 预防和治疗TrkB脑转移。

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.