Expression of cell cycle-regulatory proteins rb, p16/MTS1, p27/KIP1, p21/WAF1, cyclin D1 and cyclin E in breast cancer: correlations with expression of activating protein-1 family members.
The activating protein-1 (AP-1) complex is a mitogen-activated composite transcription factor that leads to activation of various target genes and enhanced proliferation of many cells after stimulation by TPA, EGF, serum, etc. The molecular mechanism of cell-cycle activation by AP-1 complexes remains unclear. Therefore, we studied protein expression of 6 cell cycle-regulatory proteins (Rb, p16, p21, p27, cyclin D1, and cyclin E) in protein extracts from 53 breast cancer samples and 4 mammary cell lines and correlated the data with expression of the 7 AP-1 family members (c-jun, junB, junD, c-fos, fosB, fra-1, and fra-2) as determined in a previous study. After Western blot analysis, we found significant associations between members of both groups: whereas c-jun was associated with Rb expression (p = 0.002), strong junD and c-fos expression correlated with high cyclin E reactivity (p = 0.017 and p = 0.013, respectively). Over-expression of fosB was found mainly in tumors with strong Rb (p = 0.013) and weak p16 (p = 0.004) expression. Fra-1 expression was significantly associated with p16 and cyclin E over-expression, whereas fra-2 results correlated with both cyclin D1 and cyclin E. These results point to direct or indirect activation of some cell cycle-regulatory proteins by AP-1 complexes. In addition, our data suggest differential regulation of cell cycle-stimulating and -inhibiting factors depending on the abundance of single AP-1 family members.
Department of Gynecopathology, Institute of Pathology, University Hospital Eppendorf, Hamburg, Germany. milde@uke.uni-hamburg.de
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Milde-Langosch
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Bamberger
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Methner
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Rieck
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Löning
D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D018567:Breast Neoplasms, Male / Q000378:metabolism / Q000473:pathology; D018797:Cell Cycle Proteins / Q000096:biosynthesis*; D019938:Cyclin D1 / Q000096:biosynthesis; D019927:Cyclin E / Q000096:biosynthesis; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000096:biosynthesis; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D016213:Cyclins / Q000096:biosynthesis; D005260:Female; D006367:HeLa Cells; D006801:Humans; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000096:biosynthesis; D008297:Male; D008869:Microtubule-Associated Proteins / Q000096:biosynthesis; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000096:biosynthesis*; D016160:Retinoblastoma Protein / Q000096:biosynthesis; D018808:Transcription Factor AP-1 / Q000096:biosynthesis*; D025521:Tumor Suppressor Proteins
C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D019927:Cyclin E; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D019394:Ki-67 Antigen; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D016160:Retinoblastoma Protein; D018808:Transcription Factor AP-1; D025521:Tumor Suppressor Proteins; D019938:Cyclin D1; D050760:Cyclin-Dependent Kinase Inhibitor p27