Functional Significance of Aurora Kinase A Regulatory Interactions with p53-ERα Complex in Human Breast Cancer Cells

Hiroshi Katayama, Subrata Sen

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Aurora kinase A (Aurora-A), a proto-oncogenic mitosis-regulating serine/threonine kinase, is frequently overexpressed in human breast cancer. While the kinase has been shown to cause functional inactivation of tumor suppressor protein p53, which binds estrogen receptor α (ERα) and downregulates its transcriptional activation function, significance of Aurora-A overexpression on p53 regulatory interactions in breast cancer cells has not been investigated. We describe in this report functional consequences of Aurora-A phosphorylation of p53 tumor suppressor protein on its subcellular distribution and binding with ERα that may be important in downregulating the transcription of p53-responsive growth inhibitory genes and development of resistance to DNA damage-induced apoptosis in Aurora-A overexpressing human breast cancer cells. Our results demonstrate that while estrogen activates Aurora-A expression in ERα-positive cells through ERα-GATA-3 signaling cascade, Aurora-A forms a ternary complex with p53 and ERα. Phosphorylation of p53 by Aurora-A sequesters the protein in the cytoplasm and enhances its interaction with ERα, thus repressing the transactivation functions of both p53 and ERα. These findings have significant clinical implications and suggest that prolonged estrogen exposure-mediated Aurora-A overexpression may be directly contributing to deregulated proliferation and resistance to DNA damage-induced apoptosis in breast cancer cells.

Original languageEnglish
Pages (from-to)117-124
Number of pages8
JournalHormones and Cancer
Volume2
Issue number2
DOIs
Publication statusPublished - Apr 1 2011
Externally publishedYes

Keywords

  • Aurora-A
  • Breast cancer cells
  • DNA damage-induced apoptosis
  • Estrogen receptor α
  • GATA-3
  • p53

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Oncology
  • Endocrinology
  • Endocrine and Autonomic Systems
  • Cancer Research

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