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人 研究发现，50%-60%的早期ER+乳腺癌也表达糖皮质激素受体(GR)，并且 早期乳腺癌中GR的高表达独立于 PR表达式。具体地说，在对ER+浸润性乳腺肿瘤中原发肿瘤GR表达的分析中 对1000多例ER+早期患者进行20年临床随访，发现高肿瘤GR mRNA 表达(也就是高GR活性)与显著降低复发风险相关。更多 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，从而使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可以协同调节良好的预后、抗增殖和促进肿瘤生长。 分化基因。我们建议确定GR介导的分子机制 野生型和突变型ER转录活性的调节，并定义特定的模式 ER/GR介导基因在乳腺癌中的表达在目标1中，我们将描述GR配体如何结合 结构域的激活[地塞米松(Dex)或新型选择性GR调节剂(SGRM)]影响内质网 活性，随之而来的内质网介导的基因表达，最终内质网相关的肿瘤细胞增殖。在……里面 目的2，我们将研究在地塞米松存在的情况下，GR和ER染色质和共调节因子的关联。 与新的SGRM进行比较。这将使我们更好地了解染色质的要求 修饰ER+乳腺癌增殖基因的构象和GR/ER共调控因子组装 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模型，突变体 ER表达细胞系和三苯氧胺耐药ER+模型以确定SGRM的抗肿瘤活性 确定GR调节剂最有可能有效的临床环境。加在一起，这些 实验将增加我们对乳腺癌(以及其他疾病)中GR/ER串扰的理解 激素敏感型癌症)，并有望导致新的GR靶向治疗， 利用我们在ER+/GR+乳腺癌中发现的GR调节后的抗增殖活性。

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.