This Article Full Text Full Text (PDF) Supplementary Data Alert me when this article is cited Alert me if a correction is posted Services 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 Guo, W.-J. Articles by Dimri, G. P. Search for Related Content PubMed PubMed Citation Articles by Guo, W.-J. Articles by Dimri, G. P.

Mel-18 Acts as a Tumor Suppressor by Repressing Bmi-1 Expression and Down-regulating Akt Activity in Breast Cancer Cells

¹ Division of Cancer Biology and Department of Medicine, ENH Research Institute; ² Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine; ³ Department of Biochemistry, Molecular Biology and Cell Biology, Northwestern University, Evanston, Illinois; and ⁴ State Key Laboratory of Oncology in Southern China and Departments of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou, China

Requests for reprints: Goberdhan P. Dimri, ENH Research Institute, 1001 University Place, Evanston, IL 60201. Phone: 224-364-7521; Fax: 224-364-7402; E-mail: gdimri{at}enh.org or g-dimri{at}northwestern.edu.

The Bmi-1 oncogene is overexpressed in a number of malignancies including breast cancer. In addition to Bmi-1, mammalian cells also express four other polycomb group (PcG) proteins that are closely related to Bmi-1. Virtually nothing is known about the role of these PcG proteins in oncogenesis. We have recently reported that Mel-18, a Bmi-1–related PcG protein, negatively regulates Bmi-1 expression, and that its expression negatively correlates with Bmi-1 in proliferating and senescing human fibroblasts. Here, we report that the expression of Bmi-1 and Mel-18 inversely correlates in a number of breast cancer cell lines and in a significant number of breast tumor samples. Overexpression of Mel-18 results in repression of Bmi-1 and reduction of the transformed phenotype in malignant breast cancer cells. Furthermore, the repression of Bmi-1 by Mel-18 is accompanied by the reduction of Akt/protein kinase B (PKB) activity in breast cancer cells. Similarly, Bmi-1 knockdown using RNA interference approach results in down-regulation of Akt/PKB activity and reduction in transformed phenotype of MCF7 cells. Importantly, we show that overexpression of constitutively active Akt overrides tumor-suppressive effect of Mel-18 overexpression and the knockdown of Bmi-1 expression. Thus, our studies suggest that Mel-18 and Bmi-1 may regulate the Akt pathway in breast cancer cells, and that Mel-18 functions as a tumor suppressor by repressing the expression of Bmi-1 and consequently down-regulating Akt activity. [Cancer Res 2007;67(11):5083–9]

This article has been cited by other articles:

				J. Godlewski, M. O. Nowicki, A. Bronisz, S. Williams, A. Otsuki, G. Nuovo, A. RayChaudhury, H. B. Newton, E. A. Chiocca, and S. Lawler Targeting of the Bmi-1 Oncogene/Stem Cell Renewal Factor by MicroRNA-128 Inhibits Glioma Proliferation and Self-Renewal Cancer Res., November 15, 2008; 68(22): 9125 - 9130. [Abstract] [Full Text] [PDF]

				D. Douglas, J. H.-R. Hsu, L. Hung, A. Cooper, D. Abdueva, J. van Doorninck, G. Peng, H. Shimada, T. J. Triche, and E. R. Lawlor BMI-1 Promotes Ewing Sarcoma Tumorigenicity Independent of CDKN2A Repression Cancer Res., August 15, 2008; 68(16): 6507 - 6515. [Abstract] [Full Text] [PDF]

				J.-Y. Lee, K.-S. Jang, D.-H. Shin, M.-Y. Oh, H.-J. Kim, Y. Kim, and G. Kong Mel-18 Negatively Regulates INK4a/ARF-Independent Cell Cycle Progression via Akt Inactivation in Breast Cancer Cancer Res., June 1, 2008; 68(11): 4201 - 4209. [Abstract] [Full Text] [PDF]

				S. Datta, M. J. Hoenerhoff, P. Bommi, R. Sainger, W.-J. Guo, M. Dimri, H. Band, V. Band, J. E. Green, and G. P. Dimri Bmi-1 Cooperates with H-Ras to Transform Human Mammary Epithelial Cells via Dysregulation of Multiple Growth-Regulatory Pathways Cancer Res., November 1, 2007; 67(21): 10286 - 10295. [Abstract] [Full Text] [PDF]