Estrogen and glucocorticoid receptor crosstalk in ER+ breast

项目摘要 大约70%的浸润性乳腺癌表达雌激素受体α（ER）。我们的实验室和其他 发现50-60%的早期ER+乳腺癌也表达糖皮质激素受体（GR）， GR高表达为早期乳腺癌提供了有利的预后信息， PR表达。具体地说，在分析ER+浸润性乳腺肿瘤中的原发性肿瘤GR表达时， 我们对1000多例ER+早期患者进行了20年以上的临床随访，发现高肿瘤GR mRNA 高表达（暗示高GR活性）与显著降低的复发风险相关。更 最近，我们发现在ER+乳腺癌细胞系模型中，GR激活重塑染色质，使ER- 染色质结合和ER靶基因表达显著改变。根据这些数据，我们 假设ER和GR可以提供良好预后、抗增殖和促增殖协调调节， 分化基因我们建议确定GR介导的分子机制， 调节野生型和突变型ER转录活性，并确定 乳腺癌中ER/GR介导的基因表达在目标1中，我们将描述GR配体结合 域激活[通过地塞米松（dex）或新型选择性GR调节剂（SGRM）]影响ER 活性，随后ER介导的基因表达，最终ER相关的肿瘤细胞增殖。在 目的2，我们将研究GR和ER染色质和共调节子在dex存在下的相关性。 与新型SGRM相比。这将使我们更好地了解染色质的要求 构象和GR/ER共调节子组装修饰ER+乳腺癌增殖基因 表情最后，在目标3中，我们将使用体内ER+乳腺癌患者来源的异种移植物模型，突变体ER+乳腺癌患者来源的异种移植物模型。 ER表达细胞系和他莫昔芬耐药ER+模型，以确定SGRM的抗肿瘤活性， 定义GR调节剂最有可能有效的临床背景。所有这些 实验将增加我们对乳腺癌中GR/ER串扰的理解（可能还有其他 子宫内膜敏感性癌症（如子宫内膜癌），并有望产生新的GR靶向疗法， 利用我们在ER+/GR+乳腺癌中GR调节后的抗增殖活性的发现。

PROJECT ABSTRACT Approximately 70% of invasive breast cancer expresses estrogen receptor-alpha (ER). Our lab and others have found that 50-60% of early-stage ER+ breast cancers also express glucocorticoid receptor (GR), and that high GR expression provides favorable prognostic information in early-stage breast cancer independently of PR expression. Specifically, in an analysis of primary tumor GR expression in ER+ invasive breast tumors from over 1000 ER+ early-stage patients with >20 year clinical follow-up, we discovered that high tumor GR mRNA expression (and by implication, high GR activity) was associated with a significantly lower risk of relapse. More recently, we found that in ER+ breast cancer cell line models, GR activation remodels chromatin so that ER- chromatin association and ER-target gene expression are significantly altered. Based on these data, we hypothesize that ER and GR can provide coordinated regulation of good prognosis, anti-proliferative and pro- differentiation genes. We propose to determine the molecular mechanisms underlying GR-mediated modulation of both wild-type and mutant ER transcriptional activity, and to define the specific patterns of ER/GR-mediated gene expression in breast cancer. In Aim 1, we will characterize how GR ligand binding domain activation [by either dexamethasone (dex) or novel selective GR modulators (SGRMs)] affects ER activity, consequent ER-mediated gene expression, and ultimately ER-associated tumor cell proliferation. In Aim 2, we will investigate GR and ER chromatin and co-regulator association in the presence of dex in comparison to the novel SGRMs. This will allow us to better understand the requirements of chromatin conformation and GR/ER co-regulator assembly in modifying ER+ breast cancer's proliferative gene expression. Finally, in Aim 3, we will use in vivo ER+ breast cancer patient-derived xenograft models, mutant ER-expressing cell lines, and tamoxifen-resistant ER+ models to define SGRM anti-tumor activity with the aim of defining clinical contexts in which GR modulators are most likely to be effective. Together, these experiments will both increase our understanding of GR/ER crosstalk in breast cancer (and possibly other hormone-sensitive cancers e.g. endometrial) and are expected to lead to new GR-targeted therapies that harness our discovery of anti-proliferative activity following GR modulation in ER+/GR+ breast cancer.