Steroid receptor coactivator-3 (SRC-3) is the second most overexpressed oncogenes and high SRC-3 expression correlates well with resistance to therapy and reduces disease free survival. In contrast, expression of tumor suppressor miR-34a is suppressed in cancer stem cells (CSCs), and re-expression of miR-34a inhibits CSCs function. Elucidating how expression of miR-34a is suppressed in CSCs is clearly important. In this application, we focus on the regulation of miR-34a by SRC-3 and its role in cancer progression. Interestingly, SRC-3 functions as a 'corepressor'and not a 'coactivator'to suppress miR-34a expression. 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 the disease state of breast cancer. This is the first report of a 'corepressor'function of SRC-3, the significance and the mechanism whereby SRC-3 functions as a 'corepressor'to suppress expression of miR-34a remains to be identified. Our central hypothesis is that SRC-3 functions as a 'corepressor'in a context- and signaling-dependent manner to suppress miR-34a expression and promote CSCs activity. The objective of this application is to identify the mechanism which dictates the 'corepressor'function of SRC-3, and to demonstrate the role of SRC-3-miR-34a pathway in CSCs. We will achieve our objective by pursuing two aims.
Aim 1. Identify a 'corepressor'activity from oncogenic coactivator SRC-3. Despite its importance as a tumor suppressor, how expression of miR-34a is suppressed in CSCs is not known. To understand how miR-34a is suppressed by SRC-3, transcription repressor regulatory factor X1 (RFX1) and de- phosphorylation of SRC-3 at S505 were identified as potential determinants for the 'corepressor'function of SRC-3. This is the first report of a 'corepressor'activity from an oncogenic 'coactivator'SRC-3, our objective is to elucidate the mechanism by which de-phosphorylation of SRC-3 at S505 dictates its 'corepressor'function with RFX1 to suppress miR-34a expression.
Aim 2. Define the function of SRC-3 'corepressor'activity. MiR-34a is an important tumor suppressor that inhibits CSCs function. SRC-3 and RFX1 are identified to be novel suppressors of miR-34a expression. Our objective of this aim is to demonstrate that the 'corepressor'activity of SRC-3 with RFX1 promotes CSCs function by suppressing miR-34a expression. Our study is highly innovative and significant. It demonstrates that SRC-3 functions as a 'corepressor'in the CSCs-enriched niche to promote CSCs function by suppressing miR-34a. It is the first to reveal the 'corepressor'function of SRC-3 depends on transcriptional repressor RFX1 and its own de-phosphorylation. Our study uncovers a novel 'corepressor'activity that governs the function of SRC-3 in CSCs. This is a significant step toward our long-term goal of identifying a targetable SRC-3 CSCs pathway that will be instrumental for development of anti-CSCs therapy to improve treatment response and survival of cancer patients.
This application identifies a novel SRC-3 oncogene pathway that regulates activity of cancer stem cells. Our study is highly relevant to human health and NIH's mission because the knowledge gained in this study is key to the development of new anti-cancer therapies. It will have a significant impact on the quality of life and survival of caner patients.