Abstract
In an attempt to identify subtypes of breast cancer and pinpoint patterns of cell cycle regulatory defects associated with clinical behaviour, proliferation and other transformation associated events, a multitude of cell cycle regulatory proteins were analysed in a material of 113 primary breast cancers. Increased proliferation was observed in two different scenarios; (1) with high cyclin D1 and elevated retinoblastoma protein (pRb) phosphorylation, (cyclin D1high tumours) or (2) with high cyclin E protein but low cyclin D1 and lack of corresponding pRb phosphorylation (cyclin Ehigh tumours) indicative of an interrupted pRb pathway. Characteristic for cyclin Ehigh tumours were further defects in p53, p27 and bcl-2, while c-erbB2 overexpression and c-myc amplification was found in both cyclin D1high and Ehigh tumours. Using transfected cell lines overexpressing cyclin E, cyclin Ehigh and D1high tumours were mimicked and the cyclin D1high cell line normalized the cyclin E kinase activity by an induction and redirection of p21 and p27 to the cyclin E complex whereas cyclin Ehigh cell lines obtained increased kinase activity without redirection of inhibitors. Based on differences in genetic aberrations as well as function of the pRb node we therefore propose a model in which cyclin D1high and cyclin Ehigh tumours represent two alternative mechanisms to inactivate the pRb pathway and thereby achieve unrestrained growth in the tumorogenesis of breast cancer.
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Acknowledgements
We would like to thank Bodil Bäcklund, Britta Lindgren, Elise Nilsson and Roland Rosquist for skilful technical assistance and Anna Terese Lauverud for immunohistochemical evaluations. This work was supported by grants from the Swedish Cancer Society, Malmö Cancer, Malmö Hospital and Lund University funds and Lion's research foundation, Umeå University.
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Lodén, M., Stighall, M., Nielsen, N. et al. The cyclin D1 high and cyclin E high subgroups of breast cancer: separate pathways in tumorogenesis based on pattern of genetic aberrations and inactivation of the pRb node. Oncogene 21, 4680–4690 (2002). https://doi.org/10.1038/sj.onc.1205578
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DOI: https://doi.org/10.1038/sj.onc.1205578
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