title: Cdk2-null mice are resistant to ErbB-2-induced mammary tumorigenesis.
abstract: The concept of targeting G(1) cyclin-dependent kinases (CDKs) in breast cancer treatments is supported by the fact that the genetic ablation of Cdk4 had minimal impacts on normal cell proliferation in majority of cell types, resulting in near-normal mouse development, whereas such loss of Cdk4 completely abrogated ErbB-2/neu-induced mammary tumorigenesis in mice. In most human breast cancer tissues, another G(1)-regulatory CDK, CDK2, is also hyperactivated by various mechanisms and is believed to be an important therapeutic target. In this report, we provide genetic evidence that CDK2 is essential for proliferation and oncogenesis of murine mammary epithelial cells. We observed that 87% of Cdk2-null mice were protected from ErbB-2-induced mammary tumorigenesis. Mouse embryonic fibroblasts isolated from Cdk2-null mouse showed resistance to various oncogene-induced transformation. Previously, we have reported that hemizygous loss of Cdc25A, the major activator of CDK2, can also protect mice from ErbB-2-induced mammary tumorigenesis [Cancer Res (2007) 67(14): 6605-11]. Thus, we propose that CDC25A-CDK2 pathway is critical for the oncogenic action of ErbB-2 in mammary epithelial cells, in a manner similar to Cyclin D1/CDK4 pathway.
authors.affiliation: Molecular Pharmacology & Biological Chemistry, Northwestern University, Chicago, IL 60611, USA. dipray@umich.edu
authors.forename: Dipankar
authors.initials: D
authors.lastname: Ray
authors.forename: Yasuhisa
authors.initials: Y
authors.lastname: Terao
authors.forename: Konstantin
authors.initials: K
authors.lastname: Christov
authors.forename: Philipp
authors.initials: P
authors.lastname: Kaldis
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Kiyokawa
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D002478:Cells, Cultured; D051357:Cyclin-Dependent Kinase 2 / Q000172:deficiency / Q000378:metabolism*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*
chemical_list: D051357:Cyclin-Dependent Kinase 2; D018719:Erb-b2 Receptor Tyrosine Kinases; C524056:Erbb2 protein, mouse