Corepressor Function of Steroid Receptor Coactivator-3 in Breast Cancer

乳腺癌中类固醇受体辅激活因子 3 的辅抑制功能

• 批准号: 8888409
• 负责人: Ray-Chang Wu
• 金额: $ 34.81万
• 依托单位: GEORGE WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-15 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8888409
• 关键词: Address; Breast Cancer Treatment; Cell Survival; Cell physiology; Colorectal Cancer; Deacetylation; Development; Diagnosis; Disease; Goals; HDAC1 gene; HDAC7 histone deacetylase; Health; Heat-Shock Proteins 70; Human; Indolent; Knowledge; Malignant Neoplasms; Malignant neoplasm of prostate; Mission; Molecular; Molecular Profiling; NCOA3 gene; Oncogenes; Oncogenic; Pathway interactions; Phosphorylation; Play; Resistance; Role; Signal Transduction; Somatic Cell; Staging; Transcription Coactivator; Transcription Repressor/Corepressor; Tumor Suppressor Proteins; aggressive therapy; cancer stem cell; driving force; embryonic stem cell; innovation; interest; malignant breast neoplasm; novel; overexpression; public health relevance; resistance mechanism; stem cell therapy; targeted cancer therapy; therapy resistant; tumor; Address; Breast Cancer Treatment; Cell Survival; Cell physiology; Colorectal Cancer; Deacetylation; Development; Diagnosis; Disease; Goals; HDAC1 gene; HDAC7 histone deacetylase; Health; Heat-Shock Proteins 70; Human; Indolent; Knowledge; Malignant Neoplasms; Malignant neoplasm of prostate; Mission; Molecular; Molecular Profiling; NCOA3 gene; Oncogenes; Oncogenic; Pathway interactions; Phosphorylation; Play; Resistance; Role; Signal Transduction; Somatic Cell; Staging; Transcription Coactivator; Transcription Repressor/Corepressor; Tumor Suppressor Proteins; aggressive therapy; cancer stem cell; driving force; embryonic stem cell; innovation; interest; malignant breast neoplasm; novel; overexpression; public health relevance; resistance mechanism; stem cell therapy; targeted cancer therapy; therapy resistant; tumor

 DESCRIPTION (provided by applicant): Steroid receptor coactivator-3 (SRC-3) is the second most overexpressed oncogene that plays a significant role in the development of breast cancer. Despite its importance as an oncogene, whether and how SRC-3 promotes cancer stem cells (CSCs) activity to drive aggressive cancer development remains unknown. In this application, we address the challenge of understanding how SRC-3 drives aggressive breast cancer development, and uncover a novel and unexpected mechanism for the function of SRC-3 in CSCs. Interestingly, SRC-3 functions as a corepressor and not a coactivator to suppress expression of miR-34a, a critical suppressor of CSCs' activity. Expression of SRC-3 is positively correlated with tumor grades and stages, but inversely correlated with expression of miR-34a in breast cancer, suggesting a causal relationship between SRC-3 and miR-34a expression and disease state. Our study identifies the first corepressor activity of SRC-3, and SRC-3 as the first suppressor of miR-34a expression in CSCs. Our hypothesis is that SRC-3 functions as a corepressor in a context- and signaling-dependent manner to promote CSCs activity. The objective of this application is to identify the mechanism which dictates the corepressor function of SRC-3, and to elucidate the significance of this corepressor function in the progression of breast cancer. We propose three aims to achieve our objective. Aim 1. Elucidate the mechanism for the unexpected corepressor function of SRC-3. To understand how miR-34a is suppressed, transcription repressor regulatory factor X1 (RFX1) and de-phosphorylation of SRC-3 at S505 were identified as potential determinants for the suppression of miR-34a in CSCs. Our objective is to elucidate how de-phosphorylation of S505 dictates the suppression of miR-34a by SRC-3 and RFX1 in CSCs. Aim 2. Determine the function of SRC-3 S505 de-phosphorylation in cancer stem cells. SRC-3 and RFX1 are identified to be novel suppressors of miR-34a, and importantly, suppression of miR-34a requires de-phosphorylation of SRC-3 S505. The objective of this aim is to demonstrate that de-phosphorylation of S505 plays an important role in the ability of SRC-3/RFX1 to promote CSCs function. Aim 3. Elucidate the functional importance of HSP70 K246 deacetylation. CSCs play an important role in therapy resistance. Elucidating the therapy resistant mechanism of SRC-3-miR-34a CSCs pathway is clearly important. We identified HDAC1 and HDAC7 as novel targets of miR-34a, and showed that HDACs1 and 7 deacetylate HSP70 at K246. Our objective is to demonstrate that HDACs1 and 7 promote the therapy resistant activity of SRC-3-miR-34a CSCs pathway by deacetylating HSP70 K246, and to identify the resistant mechanism of K246 deacetylation. Our study is innovative. It uncovers a novel corepressor activity that governs the function of oncogenic coactivator SRC-3 in CSCs, and reveals an important role of transcriptional repressor RFX1 and de-phosphorylation of S505. Our study is expected to have a significant impact on the diagnosis and development of targeted cancer therapy to treat aggressive and therapy resistant breast cancer.

 描述（由应用提供）：类固醇受体共激活剂3（SRC-3）是第二高表达的癌基因，在乳腺癌的发展中起着重要作用。尽管它作为癌基因的重要性，但SRC-3是否以及如何促进癌症干细胞（CSC）活性以促进侵略性癌症发展仍然未知。在此应用中，我们应对了解SRC-3如何驱动侵略性乳腺癌发展的挑战，并发现SRC-3在CSC中功能的新颖而意想不到的机制。有趣的是，SRC-3充当核压剂，而不是抑制MiR-34a表达的共激活因子，MiR-34a是CSC活性的关键抑制器。 SRC-3的表达与肿瘤成绩和阶段呈正相关，但与乳腺癌中miR-34a的表达成反比，表明SRC-3与miR-34a表达与疾病状态之间存在因果关系。我们的研究确定了SRC-3的第一个核心压力活性，而SRC-3是第一个 miR-34a在CSC中表达的抑制剂。我们的假设是，SRC-3在上下文和信号依赖性方式中充当核心，以促进CSC活动。该应用的目的是确定决定SRC-3核心函数的机制，并阐明该核心函数在乳腺癌进展中的重要性。我们提出三个目标以实现我们的目标。 AIM 1。阐明SRC-3的意外核心函数的机制。为了了解如何抑制miR-34a，转录反射器调节因子X1（RFX1）和SRC-3在S505处的去磷酸化被确定为CSC中miR-34a抑制miR-34a的潜在决定剂。我们的目的是阐明SRC-3和RFX1在CSC中的降低S505的去磷酸化如何决定miR-34a的抑制。 AIM 2。确定癌症干细胞中SRC-3 S505去磷酸化的功能。 SRC-3和RFX1被确定为miR-34a的新颖补充剂，重要的是，miR-34a的抑制需要SRC-3 S505的去磷酸化。此目的的目的是证明S505的去磷酸化在SRC-3/RFX1促进CSC功能的能力中起着重要作用。 AIM 3。阐明HSP70 K246脱乙酰化的功能重要性。 CSC在耐治疗中起着重要作用。阐明SRC-3-MIR-34A CSCS途径的耐药机制显然很重要。我们将HDAC1和HDAC7鉴定为miR-34a的新靶标，并表明HDACS1和7脱乙酰酸HSP70在K246处。我们的目标是证明HDACS1和7通过脱乙酰基HSP70 K246促进了SRC-3-MIR-34A CSCS途径的耐药活性，并确定K246脱乙酰基的耐药机制。我们的研究是创新的。它发现了一种新型的核压力活性，该活性控制着CSC中致癌共激活因子SRC-3的功能，并揭示了转录表示RFX1和S505的去磷酸化的重要作用。我们的研究预计将对靶向癌症治疗的诊断和发展产生重大影响，以治疗侵袭性和抗治疗性乳腺癌。