Interleukin-6/Stat3 regulation of the Estrogen Receptor Alpha in Breast Cancer

Interleukin-6/Stat3 对乳腺癌雌激素受体α的调节

• 批准号: 8625633
• 负责人: Jennifer Ebele Nnoli
• 金额: $ 1.76万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-12-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8625633
• 关键词: African; African American; Breast; Breast Cancer Cell; Cancer cell line; Development; EMSA; Embolism; Epigenetic Process; Estrogen Antagonists; Estrogen Receptor alpha; Estrogen Receptors; Estrogen receptor negative; Estrogen receptor positive; FDA approved; Genes; Genetic Polymorphism; Growth Factor; Inflammatory; Interleukin-6; Laboratories; Lead; Link; Mammary Neoplasms; Mammary Tumorigenesis; Mediating; Memorial Sloan-Kettering Cancer Center; Methylation; Modification; Molecular; Neoplasm Metastasis; Pathway interactions; Patients; Planning Techniques; Receptor Gene; Regulation; Relative (related person); Role; Sampling; Services; Signal Transduction; Tamoxifen; Transcriptional Regulation; Visit; Work; breast tumorigenesis; cytokine; effective therapy; gene repression; innovation; interest; malignant breast neoplasm; novel; outreach; promoter; protein distribution; public health relevance; receptor expression; tumor; tumor growth; tumor progression

DESCRIPTION (provided by applicant): We are interested in understanding the role of IL-6 in breast tumor growth and metastasis. Recent studies have linked IL-6 as a potent growth factor in estrogen receptor (ER) positive breast cancers. Studies from our lab and others have shown that IL-6 and pStat3 (a primary target of IL-6 signaling) are highly expressed in tumor emboli and on the edge of tumors - "the invasive front". Also, our preliminary work on IL-6 and ER positive breast cancer cell lines has shown that when IL-6 is highly expressed, the levels of ER decrease. A principal mechanism by which the ER is regulated is through epigenetic changes including promoter methylation. We hypothesize that the IL-6/pStat3 pathway modulates ER expression, which alters breast cancer progression and responsiveness to therapy. The work proposed here will reveal a novel role for the IL-6/Jak/Stat3 pathway in modulating ER expression through epigenetic modification of the ER promoter and may lead to targeted therapies for breast cancer. My aims include: 1. Examine the role of IL-6/Stat3 mediated ER regulation. We will determine whether ER positive breast cancer cell lines can be made ER negative through Stat3 transcriptional repression of the ER1 gene and whether sustained IL-6 signaling can lead to loss of ER expression through pStat3/DNMT1 ER1 promoter methylation promoter methylation. 2. Determine whether a correlation exist between IL-6/pStat3 expression and ER levels in primary breast tumors with a focus on the distribution of these proteins on the leading edge and in tumor emboli. We are also interested in determining whether a) the -174G>C polymorphism is associated with higher IL-6 levels within the tumor and b) whether these tumors are ER negative.

描述（由申请人提供）：我们有兴趣了解 IL-6 在乳腺肿瘤生长和转移中的作用。最近的研究表明 IL-6 是雌激素受体 (ER) 阳性乳腺癌的有效生长因子。我们实验室和其他实验室的研究表明，IL-6 和 pStat3（IL-6 信号传导的主要靶标）在肿瘤栓子和肿瘤边缘（“侵入前沿”）高度表达。此外，我们对 IL-6 和 ER 阳性乳腺癌细胞系的初步研究表明，当 IL-6 高表达时，ER 水平降低。 ER 调节的主要机制是通过表观遗传变化，包括启动子甲基化。我们假设 IL-6/pStat3 通路调节 ER 表达，从而改变乳腺癌进展和对治疗的反应。这里提出的工作将揭示 IL-6/Jak/Stat3 通路通过 ER 启动子的表观遗传修饰调节 ER 表达的新作用，并可能导致乳腺癌的靶向治疗。我的目标包括： 1. 检查 IL-6/Stat3 介导的 ER 调节的作用。我们将确定 ER 阳性乳腺癌细胞系是否可以通过 Stat3 对 ER1 基因的转录抑制而变为 ER 阴性，以及持续的 IL-6 信号传导是否可以通过 pStat3/DNMT1 ER1 启动子甲基化导致 ER 表达丧失。 2. 确定原发性乳腺肿瘤中 IL-6/pStat3 表达与 ER 水平之间是否存在相关性，重点关注这些蛋白质在前缘和肿瘤栓子中的分布。我们还有兴趣确定 a) -174G>C 多态性是否与肿瘤内较高的 IL-6 水平相关，以及 b) 这些肿瘤是否为 ER 阴性。