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Research Articles: Therapeutics, Targets, and Development

Transactivator of transcription–tagged cell cycle and apoptosis regulatory protein-1 peptides suppress the growth of human breast cancer cells in vitro and in vivo

¹ Veterans Affairs Medical Center, Departments of ² Internal Medicine, ³ Surgery, and ⁴ Pathology, ⁵ Karmanos Cancer Institute, Wayne State University, Detroit, Michigan

Requests for reprints: Arun K. Rishi, Room B4334, VA Medical Center, 4646 John R., Detroit, MI 48201. Phone: 313-576-4492; Fax: 313-576-1112. E-mail: Rishia{at}Karmanos.org

Abstract

Deregulated signaling by the epidermal growth factor receptor family of proteins is encountered in human malignancies including breast cancer. Cell cycle and apoptosis-regulatory protein-1 (CARP-1), a novel, perinuclear phosphoprotein, is a regulator of apoptosis signaling by epidermal growth factor receptors. CARP-1 expression is diminished in human breast cancers, and correlates inversely with human breast cancer grades which could be attributed to increased methylation. The expression of CARP-1, on the other hand, interferes with the ability of human breast cancer cells to invade through the matrigel-coated membranes, to form colonies in the soft agar, and to grow as s.c. tumors in severe combined immunodeficiency (SCID) mice. To test whether CARP-1 is a suppressor of human breast cancer growth, we generated transactivator of transcription (TAT)–tagged CARP-1 peptides. Treatment of human breast cancer cells with affinity purified, TAT-CARP-1 1–198, 197–454, and 896–1150 peptides caused inhibition of human breast cancer cell proliferation and elevated apoptosis. In contrast, TAT-tagged enhanced green fluorescent protein or CARP-1 (1–198^Y192/F) peptide failed to inhibit cell proliferation or induce apoptosis. Apoptosis by CARP-1 peptides, with the exception of CARP-1 (1–198^Y192/F), involves the activation of p38 stress-activated protein kinase and caspase-9. Moreover, administration of TAT-CARP-1 (1–198), but not TAT-tagged enhanced green fluorescent protein or TAT-CARP-1 (1–198^Y192/F), inhibits growth of human breast cancer cell–derived tumor xenografts in SCID mice. We conclude that CARP-1 is a suppressor of human breast cancer growth, and its expression is diminished in tumors, in part, by methylation-dependent silencing. [Mol Cancer Ther 2007;6(5):1661–72]

Grant support: Susan G. Komen Foundation for Breast Cancer Research (A.K. Rishi), the medical research services of the Department of Veterans Affairs (A.K. Rishi, A. Wali, and A.P.N. Majumdar), and by NIH RO1 AG 14343 (A.P.N. Majumdar).

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.

⁶ http://www.uscnorris.com/cpgislands2/cpg.aspx

⁷ Manuscript in preparation.

Received 10/23/06; revised 2/23/07; accepted 3/ 2/07.