This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by D’Amico, M. Articles by Pestell, R. G. Search for Related Content PubMed PubMed Citation Articles by D’Amico, M. Articles by Pestell, R. G.

The Role of Ink4a/Arf in ErbB2 Mammary Gland Tumorigenesis¹

Department of Oncology, Lombardi Cancer Center, Georgetown University, Washington, D.C. 20007 [M. D., K. W., M. F., C. A., R. G. R., R. G. P.]; Departments of Developmental and Molecular Biology [D. D. V., A. T. R., M. S.] and Epidemiology and Social Medicine [A. N.], Albert Einstein College of Medicine, Bronx, New York 10461; Department of Pathology, McMaster University, West Hamilton, Ontario, L8S 4K1 Canada [W. J. M.]; Department of Cell Biology and Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, Texas [M. W.]; Division of Epidemiology and Biostatistics, Sungkyunkwan University, School of Medicine, Jangan-gu, Suwon, Kyunggi-do 440-746, Seoul, Korea [H-W. L.]; and Dana Farber Cancer Institute, Boston, Massachusetts 02115 [R. A. D.]

Most human tumors display inactivation of the p53 and the p16^INK4/pRb pathway. The Ink4a/alternative reading frame (ARF) locus encodes the p16^INK4a and p14^ARF (murine p19^ARF) proteins. p16^INK4a is deleted in 40–60% of breast cancer cell lines, and p16^INK4a inactivation by DNA methylation occurs in ≤30% of human breast cancers. In mice genetically heterozygous for p16^INK4a or Ink4a/Arf, predisposition to specific tumor types is enhanced. Ink4a/Arf^+/- mice have increased Eµ-Myc-induced lymphomagenesis and epidermal growth factor receptor-induced gliomagenesis. ErbB2 (epidermal growth factor receptor-related protein B2) is frequently overexpressed in human breast cancer and is sufficient for mammary tumorigenesis in vivo. We determined the role of heterozygosity at the Ink4a/Arf locus in ErbB2-induced mammary tunorigenesis. Compared with mouse mammary tumor virus-ErbB2 Ink4a/Arf^+/- mice, mouse mammary tumor virus-ErbB2 Ink4a/Arf^wt mammary tumors showed increased p16^INK4a, reduced Ki-67 expression, and reduced cyclin D1 protein but increased mammary tumor apoptosis with no significant change in the risk of developing mammary tumors. These studies demonstrate the contribution of Ink4a/Arf heterozygosity to tumor progression is tissue specific in vivo. In view of the important role of Ink4a/Arf in response to chemotherapy, these transgenic mice may provide a useful model for testing breast tumor therapies.

This article has been cited by other articles:

				Y. Yin, R. G. Russell, L. E. Dettin, R. Bai, Z.-L. Wei, A. P. Kozikowski, L. Kopleovich, and R. I. Glazer Peroxisome Proliferator-Activated Receptor {delta} and {gamma} Agonists Differentially Alter Tumor Differentiation and Progression during Mammary Carcinogenesis Cancer Res., May 1, 2005; 65(9): 3950 - 3957. [Abstract] [Full Text] [PDF]

				L Hilakivi-Clarke, C Wang, M Kalil, R Riggins, and R G Pestell Nutritional modulation of the cell cycle and breast cancer Endocr. Relat. Cancer, December 1, 2004; 11(4): 603 - 622. [Abstract] [Full Text] [PDF]

				M. D'Amico, K. Wu, M. Fu, M. Rao, C. Albanese, R. G. Russell, H. Lian, D. Bregman, M. A. White, and R. G. Pestell The Inhibitor of Cyclin-Dependent Kinase 4a/Alternative Reading Frame (INK4a/ARF) Locus Encoded Proteins p16INK4a and p19ARF Repress Cyclin D1 Transcription through Distinct cis Elements Cancer Res., June 15, 2004; 64(12): 4122 - 4130. [Abstract] [Full Text] [PDF]

				C. Yang, V. Ionescu-Tiba, K. Burns, M. Gadd, L. Zukerberg, D. N. Louis, D. Sgroi, and E. V. Schmidt The Role of the Cyclin D1-Dependent Kinases in ErbB2-Mediated Breast Cancer Am. J. Pathol., March 1, 2004; 164(3): 1031 - 1038. [Abstract] [Full Text] [PDF]

				K. Wu, Y. Yang, C. Wang, M. A. Davoli, M. D'Amico, A. Li, K. Cveklova, Z. Kozmik, M. P. Lisanti, R. G. Russell, et al. DACH1 Inhibits Transforming Growth Factor-{beta} Signaling through Binding Smad4 J. Biol. Chem., December 19, 2003; 278(51): 51673 - 51684. [Abstract] [Full Text] [PDF]