Constitutive MEK/MAPK Activation Leads to p27Kip1 Deregulation and Antiestrogen Resistance in Human Breast Cancer Cells

Jeffrey C H Donovan, Andrea Milic, Joyce M Slingerland

Research output: Contribution to journalArticle

121 Citations (Scopus)

Abstract

Antiestrogens, such as the drug tamoxifen, inhibit breast cancer growth by inducing cell cycle arrest. Antiestrogens require action of the cell cycle inhibitor p27Kip1 to mediate G1 arrest in estrogen receptor-positive breast cancer cells. We report that constitutive activation of the mitogen-activated protein kinase (MAPK) pathway alters p27 phosphorylation, reduces p27 protein levels, reduces the cdk2 inhibitory activity of the remaining p27, and contributes to antiestrogen resistance. In two antiestrogen-resistant cell lines that showed increased MAPK activation, inhibition of the MAPK kinase (MEK) by addition of U0126 changed p27 phosphorylation and restored p27 inhibitory function and sensitivity to antiestrogens. Using antisense p27 oligonucleotides, we demonstrated that this restoration of antiestrogen-mediated cell cycle arrest required p27 function. These data suggest that oncogene-mediated MAPK activation, frequently observed in human breast cancers, contributes to antiestrogen resistance through p27 deregulation.

Original languageEnglish
Pages (from-to)40888-40895
Number of pages8
JournalJournal of Biological Chemistry
Volume276
Issue number44
DOIs
StatePublished - Nov 2 2001
Externally publishedYes

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Estrogen Receptor Modulators
Deregulation
Mitogen-Activated Protein Kinase Kinases
Mitogen-Activated Protein Kinases
Chemical activation
Cells
Breast Neoplasms
Phosphorylation
Cell Cycle Checkpoints
Antisense Oligonucleotides
Tamoxifen
Oncogenes
Oligonucleotides
Estrogen Receptors
Restoration
Cell Cycle
Cell Line
Growth
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Biochemistry

Cite this

Constitutive MEK/MAPK Activation Leads to p27Kip1 Deregulation and Antiestrogen Resistance in Human Breast Cancer Cells. / Donovan, Jeffrey C H; Milic, Andrea; Slingerland, Joyce M.

In: Journal of Biological Chemistry, Vol. 276, No. 44, 02.11.2001, p. 40888-40895.

Research output: Contribution to journalArticle

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