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是雌激素受体（ER）阳性乳腺癌的一种有效生长因子。我们实验室和其他实验室的研究表明，IL-6和pStat 3（IL-6信号传导的主要靶点）在肿瘤栓子和肿瘤边缘（“侵袭性前沿”）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。调节ER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/pStat 3通路调节ER表达，从而改变乳腺癌的进展和对治疗的反应性。本文提出的工作将揭示IL-6/Jak/Stat 3通路通过ER启动子的表观遗传修饰在调节ER表达中的新作用，并可能导致乳腺癌的靶向治疗。我的目标包括：1.检查IL-6/Stat 3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ER 1基因的Stat 3转录抑制而使ER阴性，以及持续的IL-6信号传导是否可以通过pStat 3/DNMT 1 ER 1启动子甲基化而导致ER表达的丧失。2.确定原发性乳腺肿瘤中IL-6/pStat 3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缘和肿瘤栓子中的分布。我们也有兴趣确定a）-174 G>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。 公共卫生相关性：本文提出的工作将揭示IL-6/Jak/Stat 3通路在调节雌激素受体（ER）表达中的新作用。这表明，抑制该途径将是一种治疗ER阴性乳腺肿瘤的创新方法，使其成为ER阳性，并允许用抗雌激素如他莫昔芬进行有效治疗。因此，这项工作的结果可能导致开发用于三阴性肿瘤患者的新型靶向疗法，特别是那些表达高水平IL-6的患者。

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. PUBLIC HEALTH RELEVANCE: The work proposed here will reveal a novel role for the IL-6/Jak/Stat3 pathway in modulating estrogen receptor (ER) expression. It would suggest that inhibition of this pathway would be a innovative approach to treating ER-negative breast tumors by rendering them ER-positive and allowing for effective treatment with anti-estrogens such as Tamoxifen. Thus, the consequences of this work may lead to the development of novel targeted therapies for patients with triple negative tumors in particular those which express high levels of IL-6.