Corepressor Function of Steroid Receptor Coactivator-3 in Breast Cancer

 描述（由申请人提供）：类固醇受体共激活因子-3（SRC-3）是第二大过表达癌基因，在乳腺癌的发生中起重要作用。尽管SRC-3作为一种致癌基因很重要，但它是否以及如何促进癌症干细胞（CSC）的活性来驱动侵袭性癌症的发展仍然是未知的。在本申请中，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中功能的一种新的和意想不到的机制。有趣的是，SRC-3作为辅阻遏物而不是辅激活物来抑制miR-34a的表达，miR-34a是CSC活性的关键抑制剂。SRC-3的表达与乳腺癌的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是第一个辅阻遏物活性。 CSCs中miR-34a表达的抑制因子。我们的假设是，SRC-3作为辅阻遏物的功能，在上下文和信号依赖的方式，以促进CSC的活动。本申请的目的是鉴定决定SRC-3的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意义。我们提出三个目标来实现我们的目标。目标1。阐明SRC-3的意外辅阻遏物功能的机制。为了了解miR-34a是如何被抑制的，转录抑制物调节因子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SRC-3和RFX1在CSC中对miR-34a的抑制。目标二。确定SRC-3 S505去磷酸化在癌症干细胞中的功能。SRC-3和RFX1被鉴定为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。本研究的目的是证明S505的去磷酸化在SRC-3/RFX1促进CSC功能的能力中起重要作用。目标3：阐明HSP 70 K246去乙酰化的功能重要性。CSC在治疗抗性中起重要作用。阐明SRC-3-miR-34a CSCs通路的治疗抗性机制显然是重要的。我们鉴定了HDAC1和HDAC7作为miR-34a的新靶点，并表明HDACs 1和7在K246处使HSP 70脱乙酰化。我们的目的是证明HDACs 1和7通过去乙酰化HSP 70 K246促进SRC-3-miR-34a CSCs通路的治疗抗性活性，并确定K246去乙酰化的抗性机制。我们的研究是创新的。它揭示了一种新的辅阻遏物活性，该活性控制致癌辅激活因子SRC-3在CSC中的功能，并揭示了转录阻遏物RFX1和S505去磷酸化的重要作用。我们的研究有望对靶向癌症治疗的诊断和发展产生重大影响，以治疗侵袭性和耐药乳腺癌。

 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.