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Research Articles

Rapamycin inhibits multiple stages of c-Neu/ErbB2–induced tumor progression in a transgenic mouse model of HER2-positive breast cancer

¹ Department of Pharmacology and ² Division of General Medical Sciences-Oncology, Case Western Reserve University School of Medicine, Cleveland, Ohio

Requests for reprints: Ruth A. Keri, Department of Pharmacology, CWRU School of Medicine, 10900 Euclid Avenue, Cleveland, OH 44106-4965. Phone: 216-368-3495; Fax: 216-368-3395. E-mail: keri{at}case.edu

Abstract

Amplification of the HER2 (ErbB2, c-Neu) proto-oncogene in breast cancer is associated with poor prognosis and high relapse rates. HER2/ErbB2, in conjunction with ErbB3, signals through the Akt/phosphatidylinositol 3-kinase pathway and leads to the activation of mammalian target of rapamycin (mTOR), a critical mRNA translation regulator that controls cell growth. Gene expression analysis of mammary tumors collected from mouse mammary tumor virus-c-Neu transgenic mice revealed that mRNA levels of several mTOR pathway members were either up-regulated (p85/phosphatidylinositol 3-kinase and p70S6 kinase) or down-regulated (eIF-4E-BP1) in a manner expected to enhance signaling through this pathway. Treatment of these mice with the mTOR inhibitor rapamycin caused growth arrest and regression of primary tumors with no evidence of weight loss or generalized toxicity. The treatment effects were due to decreased proliferation, associated with reduced cyclin D1 expression, and increased cell death in primary tumors. Whereas many of the dead epithelial cells had the histopathologic characteristics of ischemic necrosis, rapamycin treatment was not associated with changes in microvascular density or apoptosis. Rapamycin also inhibited cellular proliferation in lung metastases. In summary, data from this preclinical model of ErbB2/Neu-induced breast cancer show that inhibition of the mTOR pathway with rapamycin blocks multiple stages of ErbB2/Neu-induced tumorigenic progression. [Mol Cancer Ther 2007;6(8):2188–97]

Grant support: NIH [grant RO1-CA090398 (R.A. Keri) and Case Western Reserve University Medical Scientist Training Program training grant T32-GM07250 (J.D. Mosley)], an Ohio Innovation Incentive Fellowship (J.D. Mosley), and an Endocrine Society Summer Research Fellowship (J.T. Poirier).

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: J.D. Mosley and J.T. Poirier contributed equally to this work.

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

Received 4/ 4/07; revised 5/22/07; accepted 6/12/07.

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