Modulation of STAT3 activity by STAT5 in triple negative breast cancer

三阴性乳腺癌中 STAT5 对 STAT3 活性的调节

基本信息

批准号：
10714954
负责人：
Sarah Walker
金额：
$ 18.95万
依托单位：
UNIVERSITY OF NEW HAMPSHIRE
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2028-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10714954
关键词：
ATAC-seq Address BCL6 gene Binding Binding Proteins Binding Sites Biological Biological Markers Biomedical Engineering Biotinylation Breast Cancer Cell Breast Cancer Patient Breast Cancer cell line Breast Cancer therapy CDH1 gene Cell Line Cell Proliferation Cells ChIP-seq Clinic Clustered Regularly Interspaced Short Palindromic Repeats Computer Analysis Core Facility DNA Binding Data Data Analyses Disease Event Family member Future Gene Expression Gene Expression Profile Gene Expression Regulation Genes Genetic Transcription Genome Genomics Goals Growth Human In Vitro Lead MDA MB 231 MDA-MB-468 Malignant Neoplasms Mammary Neoplasms Mass Spectrum Analysis Mediating Mediator Methods Molecular Molecular Target Pathogenesis Pathogenicity Patients Phosphotransferases Play Positioning Attribute Prognosis Proteins Regulation Research Sampling Site Stat3 protein Stat5 protein Survival Rate TFAP2C gene Testing Therapeutic Use of New Techniques Work cancer cell cancer type cell growth chemotherapy cofactor epithelial to mesenchymal transition genomic locus in vivo inhibitor malignant breast neoplasm migration mouse model mutant novel novel therapeutic intervention recruit response single-cell RNA sequencing tenure track transcription factor treatment response treatment strategy triple-negative invasive breast carcinoma tumor upstream kinase

项目摘要

PROJECT SUMMARY (Walker, Project Lead) Triple-negative breast cancer (TNBC) remains a deadly disease despite recent new treatments. Therefore, additional treatment strategies are needed. One of the main issues is the lack of a molecular target. The transcription factor STAT3 is constitutively active in many triple-negative breast cancers. While inhibitors of an upstream kinase Jak2 have been tested in the clinic, they have not shown efficacy as a single therapy. STAT3 can be activated by additional kinases which may be one reason for lack of response. Therefore, we hypothesized that targeting the activity of STAT3 may prove a useful strategy since this would target STAT3 regardless of upstream kinase. However, no STAT3 inhibitors have been approved for treatment of TNBC. Previously, we have found that activation of the related STAT family member, STAT5, in triple-negative breast cancer cells modulated STAT3 activity and reduced the growth and sensitized these cells to chemotherapy. This suggests that activating STAT5 could be a treatment for TNBC. However, as STAT5 has been shown to promote some cancers, this is not a viable option. We have found that STAT5 competes with STAT3 on DNA binding and gene regulation, suggesting that understanding the molecular effects of STAT5 on STAT3 activity could identify new inroads for TNBC therapy. Preliminary data from ChIP-seq analysis identifies a subset of binding regions within the genome that both STAT3 and STAT5 bind, particularly in regulating additional transcription factors. Directed ChIP demonstrates that while STAT3 is dominant over STAT5 on a few sites, STAT5 is dominant over STAT3 on numerous sites. This suggests that STAT5 modulates STAT3 activity by oppositely regulating several genes that may play key roles in TNBC, raising the possibility that targeting STAT3 via STAT5 activity could reduce the aggressiveness of TNBC and sensitize these cancer cells to chemotherapy. We hypothesize that defining how STAT5 modulates STAT3 may lead to new treatment strategies that mimic the effects of STAT5 on STAT3. To address this, we will carry out the following specific aims. In aim 1, we will identify genes differentially regulated by STAT3 and STAT5 in triple-negative breast cancer. In aim 2, we will assess the biological effects of a subset of genes that STAT5 and STAT3 both regulate in TNBC. In aim 3, we will use a new method to identify STAT3 and STAT5 cofactors at specific loci within the genome, providing us with a more complete understanding on the competition between STAT3 and STAT5 on gene expression. We expect to identify both the mechanism of differential gene regulation by STAT5 and STAT3 and identify key genes that are differentially regulated by STAT5 and STAT3 in TNBC. Identifying these genes may serve as biomarkers or targets for future treatment of triple-negative breast cancer by mimicking the effects of STAT5 activation on STAT3 gene regulation.

项目摘要（Walker，项目负责人）尽管最近有了新的治疗方法，三阴性乳腺癌（TNBC）仍然是一种致命的疾病。所以，需要额外的治疗策略。主要问题之一是缺乏分子靶点。这转录因子 STAT3 在许多三阴性乳腺癌中持续活跃。虽然抑制剂上游激酶 Jak2 已在临床中进行了测试，但尚未显示出作为单一疗法的功效。统计数据3 可以被额外的激酶激活，这可能是缺乏反应的原因之一。因此，我们假设针对 STAT3 的活性可能被证明是一种有用的策略，因为这将针对 STAT3 无论上游激酶如何。然而，尚无 STAT3 抑制剂被批准用于治疗 TNBC。此前，我们发现三阴性乳腺癌中相关 STAT 家族成员 STAT5 的激活癌细胞调节 STAT3 活性并减少生长并使这些细胞对化疗敏感。这表明激活 STAT5 可能是 TNBC 的治疗方法。然而，正如 STAT5 已被证明可以促进对于某些癌症，这不是一个可行的选择。我们发现 STAT5 与 STAT3 在 DNA 结合上竞争基因调控，表明了解 STAT5 对 STAT3 活性的分子影响可以确定 TNBC 治疗取得新进展。 ChIP-seq 分析的初步数据确定了结合区域的子集在 STAT3 和 STAT5 结合的基因组内，特别是在调节其他转录因子方面。定向 ChIP 表明，虽然 STAT3 在一些位点上比 STAT5 更占优势，但 STAT5 比 STAT5 更占优势。许多网站上都有 STAT3。这表明 STAT5 通过相反地调节多个 STAT3 活性来调节 STAT3 活性。可能在 TNBC 中发挥关键作用的基因，增加了通过 STAT5 活性靶向 STAT3 的可能性降低 TNBC 的侵袭性并使这些癌细胞对化疗敏感。我们假设定义 STAT5 如何调节 STAT3 可能会导致模仿 STAT5 效果的新治疗策略在 STAT3 上。针对这一问题，我们将实现以下具体目标。在目标 1 中，我们将识别基因三阴性乳腺癌中 STAT3 和 STAT5 的差异调节。在目标 2 中，我们将评估 STAT5 和 STAT3 在 TNBC 中共同调节的基因子集的生物学效应。在目标 3 中，我们将使用鉴定基因组内特定位点的 STAT3 和 STAT5 辅因子的新方法，为我们提供了更多信息全面了解STAT3和STAT5在基因表达上的竞争。我们期望确定 STAT5 和 STAT3 差异基因调控的机制，并确定关键基因 TNBC 中 STAT5 和 STAT3 的差异调节。识别这些基因可以作为生物标志物或通过模拟 STAT5 激活对三阴性乳腺癌的未来治疗目标 STAT3基因调控。