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.
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 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 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.
Lodén
Martin
M
Department of Pathology, Umeå University, S-901 87 Umeå, Sweden.
Stighall
Maria
M
Nielsen
Niels Hilmer
NH
Roos
Göran
G
Emdin
Stefan O
SO
Ostlund
Hanna
H
Landberg
Göran
G
D015153:Blotting, Western; D001943:Breast Neoplasms / Q000145:classification / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D002455:Cell Division; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism*; D019927:Cyclin E / Q000235:genetics / Q000378:metabolism*; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D005500:Follow-Up Studies; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008954:Models, Biological; D011960:Receptors, Estrogen / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction; D015996:Survival Rate; D014407:Tumor Cells, Cultured
D019927:Cyclin E; D011960:Receptors, Estrogen; D016160:Retinoblastoma Protein; D019938:Cyclin D1; D018844:Cyclin-Dependent Kinases