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EGF effects on p53 in MDA-468 human breast cancer cells: implications for G1 arrest

K A Prasad1, J G Church

  • 1Terry Fox Cancer Research Laboratories, Division of Basic Medical Sciences, Faculty of Medicine, Memorial University of Newfoundland, St John's, Canada.

Cell Proliferation
|February 1, 1997
PubMed

Insights

Epidermal growth factor (EGF) inhibits MDA-468 breast cancer cell proliferation by altering the conformation of mutant p53 protein. This change in p53 protein structure, not its levels, causes cell cycle arrest.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Cancer Research

Background:

  • Epidermal growth factor (EGF) inhibits proliferation in MDA-468 human breast cancer cells.
  • This inhibition is linked to cell cycle arrest at the G1-S boundary and reduced mRNA levels of a mutant p53 protein (p53(273.His)).
  • Mutant p53 proteins, like p53(273.His), are often associated with enhanced cell proliferation, making its role in EGF-induced arrest a key question.

Purpose of the Study:

  • To investigate the hypothesis that EGF-induced G1 arrest in MDA-468 cells is mediated by the mutant p53(273.His) protein.
  • To determine if EGF affects the conformation, protein levels, or synthesis of p53(273.His).
  • To explore the role of p53 phosphorylation and conformational changes in EGF-mediated growth inhibition.

Main Methods:

  • Immunofluorescence staining using specific antibodies (PAb 240, PAb 1620, PAb 1801) to detect conformational changes in nuclear p53(273.His).
  • Analysis of p53(273.His) protein levels and synthesis following EGF treatment.
  • Assessment of p53(273.His) phosphorylation status in EGF-treated cells.
  • Correlation of observed molecular events with cell cycle arrest.

Main Results:

  • EGF treatment induced an altered conformation of nuclear p53(273.His) without immediate changes in protein levels or synthesis.
  • A decrease in mutant-specific antibody (PAb 240) reactivity and an increase in wild-type specific antibody (PAb 1620) reactivity were observed for p53(273.His).
  • A reduction in the phosphorylation of nuclear p53(273.His) was detected in EGF-treated cells, preceding cell cycle arrest.

Conclusions:

  • EGF induces a phosphorylation-dependent conformational change in nuclear p53(273.His) in MDA-468 cells.
  • This altered p53 conformation and subsequent change in function are likely responsible for the observed EGF-dependent growth inhibition.
  • The findings suggest a novel mechanism for growth regulation in breast cancer involving EGF and mutant p53 signaling.

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