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，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) 驱动侵袭性癌症发展的活性仍然未知。在本应用中，我们解决了了解 SRC-3 如何驱动侵袭性乳腺癌发展的挑战，并揭示了一种新颖且意想不到的功能机制。 CSC 中的 SRC-3 与乳腺癌中 miR-34a 的表达呈负相关，表明 SRC-3 和 miR-34a 表达与疾病状态之间存在因果关系。 SRC-3，SRC-3作为第一个 我们的假设是，SRC-3 以背景和信号依赖的方式作为辅阻遏物发挥作用，以促进 CSC 的活性。本申请的目的是确定决定 miR-34a 的辅阻遏物功能的机制。 SRC-3，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 1. 阐明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。阐明 S505 的去磷酸化如何决定 SRC-3 和 RFX1 在 CSC 中抑制 miR-34a。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 的新型抑制剂，重要的是，抑制 miR-34a 需要 SRC-3 S505 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。 3. 阐明 HSP70 K246 去乙酰化在治疗抵抗中发挥重要作用 阐明 SRC-3-miR-34a CSC 通路的治疗抵抗机制显然很重要。 34a，并表明 HDACs1 和 7 在 K246 处使 HSP70 脱乙酰化。我们的目标是证明 HDACs1。 7 通过去乙酰化 HSP70 K246 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，它揭示了一种控制致癌共激活子功能的新型辅阻遏物活性。 SRC-3 在 CSC 中，揭示了转录抑制因子 RFX1 和 S505 去磷酸化的重要作用。预计该研究将对诊断和开发治疗侵袭性和耐药性乳腺癌的靶向癌症疗法产生重大影响。