Scholarlink

<p>Point mutations in the ligand binding domain of retinoic acid receptor alpha (RARα) are linked to breast fibroepithelial tumor development, but their role in solid tumorigenesis is unclear. In this study, we assessed the functional effects of known RARα mutations on retinoic acid signaling using biochemical and cellular assays. All tested mutants exhibited reduced transcriptional activity compared to wild-type RARα and showed a dominant negative effect, a feature associated with developmental defects and tumor formation. X-ray crystallography revealed that the mutants maintained structural integrity, with altered co-activator recruitment explaining the loss of transcriptional function. Transcriptomics and cell growth assays demonstrated that mutant RARα proteins conferred resistance to ligand-induced growth inhibition in phyllodes tumor cells. Although the mutations impair RARα’s response to retinoic acid, some mutants could be partially reactivated with synthetic agonists. These findings provide insights into how RARα mutations may contribute to tumorigenesis.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Effects of RARα ligand binding domain mutations on breast fibroepithelial tumor function and signaling

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年1月3日

查看全文
  • Xi Xiao Huang,
  • Ley Moy Ng,
  • Po-Hsien Lee,
  • Peiyong Guan,
  • Mun Juinn Chow,
  • Aisyah Binte Mohamed Bashir,
  • Meina Lau,
  • Kenric Yi Shu Tan,
  • Zhimei Li,
  • Jason Yongsheng Chan,
  • Jing Han Hong,
  • Sheng Rong Ng,
  • Tun Kiat Ko,
  • Hong Lee Heng,
  • Hsiang Ling Teo,
  • Daniela Rhodes,
  • Patrick Tan,
  • Puay Hoon Tan,
  • Donald P. McDonnell,
  • Bin Tean Teh

摘要

Point mutations in the ligand binding domain of retinoic acid receptor alpha (RARα) are linked to breast fibroepithelial tumor development, but their role in solid tumorigenesis is unclear. In this study, we assessed the functional effects of known RARα mutations on retinoic acid signaling using biochemical and cellular assays. All tested mutants exhibited reduced transcriptional activity compared to wild-type RARα and showed a dominant negative effect, a feature associated with developmental defects and tumor formation. X-ray crystallography revealed that the mutants maintained structural integrity, with altered co-activator recruitment explaining the loss of transcriptional function. Transcriptomics and cell growth assays demonstrated that mutant RARα proteins conferred resistance to ligand-induced growth inhibition in phyllodes tumor cells. Although the mutations impair RARα’s response to retinoic acid, some mutants could be partially reactivated with synthetic agonists. These findings provide insights into how RARα mutations may contribute to tumorigenesis.