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

 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（由申请人提供）：类固醇受体辅激活因子-3 (SRC-3) 是第二大过度表达的癌基因，在乳腺癌的发展中发挥着重要作用。尽管其作为癌基因很重要，但 SRC-3 是否以及如何促进癌症干细胞 (CSC) 活性以驱动侵袭性癌症发展仍不清楚。在此应用中，我们解决了理解 SRC-3 如何驱动侵袭性乳腺癌发展的挑战，并揭示了 SRC-3 在 CSC 中的功能的一种新颖且意想不到的机制。有趣的是，SRC-3 作为辅抑制子而不是共激活子来抑制 miR-34a 的表达，而 miR-34a 是 CSC 活性的关键抑制因子。乳腺癌中SRC-3的表达与肿瘤分级和分期呈正相关，但与miR-34a的表达呈负相关，表明SRC-3和miR-34a的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 的第一个辅阻遏物活性，并且 SRC-3 是第一个 CSC 中 miR-34a 表达的抑制因子。我们的假设是，SRC-3 作为辅阻遏物以上下文和信号依赖方式发挥作用，以促进 CSC 活性。本申请的目的是确定决定 SRC-3 辅阻遏物功能的机制，并阐明这种辅阻遏物功能在乳腺癌进展中的重要性。我们提出三个目标来实现我们的目标。目标 1. 阐明 SRC-3 意想不到的辅阻遏物功能的机制。为了了解 miR-34a 是如何被抑制的，转录抑制调节因子 X1 (RFX1) 和 SRC-3 在 S505 的去磷酸化被确定为抑制 CSC 中 miR-34a 的潜在决定因素。我们的目标是阐明 S505 的去磷酸化如何决定 CSC 中 SRC-3 和 RFX1 对 miR-34a 的抑制。目标 2. 确定 SRC-3 S505 去磷酸化在癌症干细胞中的功能。 SRC-3 和 RFX1 被确定为 miR-34a 的新型抑制剂，重要的是，miR-34a 的抑制需要 SRC-3 S505 的去磷酸化。该目的的目的是证明 S505 的去磷酸化在 SRC-3/RFX1 促进 CSC 功能的能力中发挥重要作用。目标 3. 阐明 HSP70 K246 脱乙酰化的功能重要性。 CSC 在治疗抵抗中发挥着重要作用。阐明 SRC-3-miR-34a CSC 通路的治疗抵抗机制显然很重要。我们将 HDAC1 和 HDAC7 确定为 miR-34a 的新靶标，并表明 HDACs1 和 7 在 K246 处使 HSP70 脱乙酰化。我们的目的是证明HDACs1和7通过HSP70 K246去乙酰化促进SRC-3-miR-34a CSCs通路的治疗抵抗活性，并确定K246去乙酰化的抵抗机制。我们的研究是创新的。它揭示了一种新的辅阻遏物活性，该活性控制着 CSC 中致癌辅激活物 SRC-3 的功能，并揭示了转录阻遏物 RFX1 和 S505 去磷酸化的重要作用。我们的研究预计将对治疗侵袭性和耐药性乳腺癌的靶向癌症治疗的诊断和开发产生重大影响。