Cdk2-null mice are resistant to ErbB-2-induced mammary tumorigenesis

Dipankar Ray; Yasuhisa Terao; Konstantin Christov; Philipp Kaldis; Hiroaki Kiyokawa

doi:10.1593/neo.101704

Cdk2-null mice are resistant to ErbB-2-induced mammary tumorigenesis

Dipankar Ray^*, Yasuhisa Terao, Konstantin Christov, Philipp Kaldis, Hiroaki Kiyokawa

^*Corresponding author for this work

Pharmacology

Research output: Contribution to journal › Article › peer-review

25 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	439-444
Number of pages	6
Journal	Neoplasia
Volume	13
Issue number	5
DOIs	https://doi.org/10.1593/neo.101704
State	Published - May 2011

Funding

Address all correspondence to: Dipankar Ray, PhD, Department of Radiation Oncology, University of Michigan, 1301 Catherine St, Med Sci I, Room 4326A, Ann Arbor, MI 48109. E-mail: [email protected]; or Hiroaki Kiyokawa, MD, PhD, Department of Molecular Pharmacology & Biological Chemistry, Northwestern University, 303 E Superior St, Lurie Bldg 3-313, Chicago, IL 60611. E-mail: [email protected] 1This work was supported in part by funds provided to H.K. by the National Institutes of Health (R01-CA100204, CA112282, and HD38085), the Searle Leadership Fund, the Zell Fund, the H Foundation, the Lynn Sage Cancer Research Foundation, the Phi Beta Psi Sorority, the Northwestern Memorial Foundation, and the Robert H. Lurie Comprehensive Cancer Center. Received 11 December 2010; Revised 17 February 2011; Accepted 23 February 2011 Copyright © 2011 Neoplasia Press, Inc. All rights reserved 1522-8002/11/$25.00 DOI 10.1593/neo.101704

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Cancer Research

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1593/neo.101704

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title = "Cdk2-null mice are resistant to ErbB-2-induced mammary tumorigenesis",

abstract = "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.",

author = "Dipankar Ray and Yasuhisa Terao and Konstantin Christov and Philipp Kaldis and Hiroaki Kiyokawa",

note = "Funding Information: Address all correspondence to: Dipankar Ray, PhD, Department of Radiation Oncology, University of Michigan, 1301 Catherine St, Med Sci I, Room 4326A, Ann Arbor, MI 48109. E-mail: [email protected]; or Hiroaki Kiyokawa, MD, PhD, Department of Molecular Pharmacology & Biological Chemistry, Northwestern University, 303 E Superior St, Lurie Bldg 3-313, Chicago, IL 60611. E-mail: [email protected] 1This work was supported in part by funds provided to H.K. by the National Institutes of Health (R01-CA100204, CA112282, and HD38085), the Searle Leadership Fund, the Zell Fund, the H Foundation, the Lynn Sage Cancer Research Foundation, the Phi Beta Psi Sorority, the Northwestern Memorial Foundation, and the Robert H. Lurie Comprehensive Cancer Center. Received 11 December 2010; Revised 17 February 2011; Accepted 23 February 2011 Copyright {\textcopyright} 2011 Neoplasia Press, Inc. All rights reserved 1522-8002/11/$25.00 DOI 10.1593/neo.101704",

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AB - 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.

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Cdk2-null mice are resistant to ErbB-2-induced mammary tumorigenesis

Abstract

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UN SDGs

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