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

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在雌激素受体（ER）阳性乳腺癌中是一种有效的生长因子。我们实验室和其他人的研究表明，IL-6和pStat3 （IL-6信号传导的主要靶点）在肿瘤栓塞和肿瘤边缘（“侵袭前沿”）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。内质网调控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，从而改变乳腺癌的进展和对治疗的反应。这项工作将揭示IL-6/Jak/Stat3通路通过内质网启动子的表观遗传修饰来调节内质网表达的新作用，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介导内质网调控的作用。我们将确定ER阳性乳腺癌细胞系是否可以通过Stat3对ER1基因的转录抑制使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表达缺失。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，重点关注这些蛋白在前沿和肿瘤栓塞中的分布。我们也有兴趣确定a) -174G>C多态性是否与肿瘤内较高的IL-6水平相关，b)这些肿瘤是否为ER阴性。

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.