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Cyclin E dependent kinase activity in human breast cancer in relation to cyclin E, p27 and p21 expression and

M Lodén1, N H Nielsen, G Roos

  • 1Department of Pathology, Umeå University, Sweden.

Oncogene
|June 3, 1999
PubMed

Insights

Breast cancer cell cycle deregulation involves cyclin E kinase activity. Inhibitory proteins p27 and p21 modulate this activity, impacting retinoblastoma protein phosphorylation and proliferation.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • Cell cycle regulation is crucial for preventing cancer.
  • Deregulation of G1-S phase transition, involving cyclin-dependent kinases, is common in tumors.
  • Enhanced cyclin-dependent kinase activity is hypothesized to drive cell cycle aberrations, but direct evidence in primary tumors is limited.

Purpose of the Study:

  • To determine cyclin E-dependent kinase activity (cyclin E(kinase)) in primary breast cancers.
  • To investigate the relationship between cyclin E(kinase), cyclin E expression, and levels of p27 and p21.
  • To assess the association of cyclin E(kinase) with retinoblastoma protein (pRb) phosphorylation and tumor proliferation.

Main Methods:

  • H1-kinase assay to measure cyclin E(kinase) in 59 primary breast cancer samples.
  • Analysis of cyclin E, p27, and p21 expression.
  • Assessment of in vivo pRb phosphorylation and proliferation markers in a subgroup of 48 tumors.

Main Results:

  • Cyclin E(kinase) positively correlated with cyclin E expression and inversely with p27 and p21 levels.
  • p27, but not p21, was linked to low cyclin E(kinase) at normal/low cyclin E levels.
  • High levels of both p21 and p27 were needed to suppress cyclin E(kinase) when cyclin E levels were elevated.
  • Cyclin E(kinase) correlated with pRb phosphorylation and proliferation, though pRb phosphorylation did not correlate with proliferation.
  • pRb phosphorylation was confirmed as a substrate for cyclin E(kinase) in primary breast cancer.

Conclusions:

  • Deregulation of cyclin E and p27 contributes to increased CDK-kinase activity in breast cancer.
  • While cyclin E and p27 influence kinase activity and pRb phosphorylation, other cyclin E-associated events may limit S-phase entry.
  • Findings highlight the complex interplay of cell cycle regulators in breast cancer progression.

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