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Research Articles: Therapeutics, Targets, and Development

Roles of human epidermal growth factor receptor 2, c-jun NH₂-terminal kinase, phosphoinositide 3-kinase, and p70 S6 kinase pathways in regulation of cyclin G2 expression in human breast cancer cells

¹ Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas and ² Department of Pharmacology, College of Medicine, The University of Iowa, Iowa City, Iowa

Requests for reprints: Robert C. Bast, Jr., Mary C. Horne, or Xiao-Feng Le, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Box 354, Houston, TX 77030-4009. Phone: 713-792-7743; Fax: 713-792-7864. E-mail: rbast{at}mdanderson.org or Phone: 319-335-8267; Fax: 319-335-8930. E-mail: mary-horne{at}uiowa.edu or Phone: 713-745-4353; Fax: 713-745-2107. E-mail: xfle{at}mdanderson.org

Abstract

The CCNG2 gene that encodes the unconventional cyclin G2 was one of the few genes up-regulated on anti–human epidermal growth factor receptor 2 (HER2) antibody–mediated inhibition of HER2 signaling. The purpose of this study was to explore how HER2 signaling modulates cyclin G2 expression and the effect of elevated cyclin G2 on breast cancer cell growth. Treatment of breast cancer cells that overexpress HER2 (BT474, SKBr3, and MDAMB453) with the anti-HER2 antibody trastuzumab or its precursor 4D5 markedly up-regulated cyclin G2 mRNA in vitro and in vivo, as shown by real-time PCR. Immunoblot and immunofluorescence analysis with specific antibodies against cyclin G2 showed that anti-HER2 antibody significantly increased cyclin G2 protein expression and translocated the protein to the nucleus. Trastuzumab was not able to induce cyclin G2 expression in cells weakly expressing HER2 (MCF7) or in cells that had developed resistance to trastuzumab. Enforced expression of HER2 in T47D and MDAMB435 breast cancer cells reduced cyclin G2 levels. Collectively, these data suggest that HER2-mediated signaling negatively regulates cyclin G2 expression. Inhibition of phosphoinositide 3-kinase (LY294002), c-jun NH₂-terminal kinase (SP600125), and mammalian target of rapamycin (mTOR)/p70 S6 kinase (p70S6K; rapamycin) increased cyclin G2 expression. In contrast, treatment with inhibitors of p38 mitogen-activated protein kinase (SB203580), mitogen-activated protein kinase/extracellular signal–regulated kinase kinase 1/2 (U0126), or phospholipase C (U73122) did not affect cyclin G2 expression. Anti-HER2 antibody in combination with LY294002, rapamycin, or SP600125 induced greater cyclin G2 expression than either agent alone. Ectopic expression of cyclin G2 inhibited cyclin-dependent kinase 2 activity, Rb phosphorylation, cell cycle progression, and cellular proliferation without affecting p27^Kip1 expression. Thus, cyclin G2 expression is modulated by HER2 signaling through multiple pathways including phosphoinositide 3-kinase, c-jun NH₂-terminal kinase, and mTOR signaling. The negative effects of cyclin G2 on cell cycle and cell proliferation, which occur without altering p27^Kip1 levels, may contribute to the ability of trastuzumab to inhibit breast cancer cell growth. [Mol Cancer Ther 2007;6(11):2843–57]

Grant support: National Cancer Institute grant CA39930 (R.C. Bast) and U.S. Army Medical Research and Materiel Command grant BC045656 (M.C. Horne).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: M.F. Horne and R.C. Bast shared equally in senior authorship.

³ Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

⁴ A.S. Arachchige-Don and M.C. Horne, unpublished data.

Received 2/16/07; revised 7/20/07; accepted 10/ 1/07.

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