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
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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 D1(high) tumours) or (2) with high cyclin E protein but low cyclin D1 and lack of corresponding pRb phosphorylation (cyclin E high tumours) indicative of an interrupted pRb pathway. Characteristic for cyclin E-high tumours were further defects in p53, p27 and bcl-2, while c-erbB2 overexpression and c-myc amplification was found in both cyclin D1(high) and E-high tumours. Using transfected cell lines overexpressing cyclin E, cyclin E-high and D1(high) tumours were mimicked and the cyclin D1(high) cell line normalized the cyclin E kinase activity by an induction and redirection of p21 and p27 to the cyclin E complex whereas cyclin E-high cell lines obtained increased kinase activity with out redirection or inhibitors. Based on differences in genetic aberrations as well as function of the pRb node we therefore propose a model in which cyclin D1(high) and cyclin E-high tumours represent two alternative mechanisms to inactivate the pRb pathway and thereby achieve unrestrained growth in the tumorogenesis of breast cancer.