Cdk2-Null Mice Are Resistant to ErbB-2-Induced Mammary Tumorigenesis

• Published in: Neoplasia Vol. 13; no. 5; pp. 439 - 444
• Main Authors: Ray, Dipankar, Terao, Yasuhisa, Christov, Konstantin, Kaldis, Philipp, Kiyokawa, Hiroaki
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.05.2011; Elsevier BV; Neoplasia Press Inc; Elsevier
• Subjects: Animals; Breast Neoplasms; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cell Proliferation; Cell Transformation, Neoplastic; Cell Transformation, Neoplastic - metabolism; Cells, Cultured; Cyclin-Dependent Kinase 2; Cyclin-Dependent Kinase 2 - deficiency; Cyclin-Dependent Kinase 2 - metabolism; Female; Fibroblasts; Fibroblasts - metabolism; Mammary Neoplasms, Experimental; Mammary Neoplasms, Experimental - genetics; Mammary Neoplasms, Experimental - metabolism; Mice; Mice, Transgenic; Neoplasms. Tumors. Oncology. Including cancer and carcinogens; Oncology; RC254-282; Receptor, ErbB-2; Receptor, ErbB-2 - metabolism
• ISSN: 1476-5586; 1522-8002; 1476-5586; 1522-8002
• DOI: 10.1593/neo.101704

The concept of targeting G1 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 G1-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.