This Article Full Text (PDF) 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 Huynh, H. Articles by Pollak, M. Search for Related Content PubMed PubMed Citation Articles by Huynh, H. Articles by Pollak, M.

Silencing of the Mammary-derived Growth Inhibitor (MDGI) Gene in Breast Neoplasms Is Associated with Epigenetic Changes¹

Lady Davis Research Institute of the Jewish General Hospital [H. H., L. A., M. P.] and Departments of Medicine [H. H., M. P.], Pathology [L. A.], and Oncology [M. P.], McGill University, Montreal, Quebec H3T 1E2, Canada

Recently, we reported that breast cancer cell lines fail to express the gene encoding the fatty acid binding protein mammary derived growth inhibitor (MDGI) and that transfection with an MDGI expression vector results in suppression of the malignant phenotype, suggesting that MDGI is a tumor suppressor gene. We also demonstrated that homozygous deletion and point mutation are not common mechanisms for silencing of the MDGI gene in human breast neoplasms. We now report that hypermethylation of HpaII and HhaI sites upstream of the first exon of the MDGI gene, and a SacII site in the first intron, occurs frequently in human breast cancer cell lines. This distinct methylation pattern is associated with loss of transcription and is reversible by treatment with 5-aza-deoxycytidine. Primary breast tumors also exhibited methylation of the SacII site (19 of 35, 54.3%) and the HpaII and HhaI sites (21 of 35, 66%). Hypermethylation of these sites was correlated with the absence of MDGI mRNA in these tumors. Our results suggest that epimutation of the MDGI gene leads to silencing, which, in turn, may initiate or contribute to progression of breast cancer.

¹ This work was supported by grants from the Canadian Breast Cancer Foundation (of Toronto, Ontario, Canada; H. H.), the National Institute of Canada (M. P.), and the Sir Mortimer B. Davis Jewish General Hospital Internal Awards Committee (L. A.).

² To whom requests for reprints should be addressed, at Lady Davis Research Institute, McGill University, 3755 Cote Ste. Catherine Road, Montreal, Quebec H3T 1E2, Canada. Phone: (514) 340-8260, ext. 3358; Fax: (514) 340-7502.

Received 7/19/96. Accepted 9/17/96.

This article has been cited by other articles:

				T. Okano, T. Kondo, K. Fujii, T. Nishimura, T. Takano, Y. Ohe, K. Tsuta, Y. Matsuno, A. Gemma, H. Kato, et al. Proteomic Signature Corresponding to the Response to Gefitinib (Iressa, ZD1839), an Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor in Lung Adenocarcinoma Clin. Cancer Res., February 1, 2007; 13(3): 799 - 805. [Abstract] [Full Text] [PDF]

				A. A. Melnikov, R. B. Gartenhaus, A. S. Levenson, N. A. Motchoulskaia, and V. V. Levenson (Chernokhvostov) MSRE-PCR for analysis of gene-specific DNA methylation Nucleic Acids Res., June 8, 2005; 33(10): e93 - e93. [Abstract] [Full Text] [PDF]

				M. Wang, Y. E. Liu, I. D. Goldberg, and Y. E. Shi Induction of Mammary Gland Differentiation in Transgenic Mice by the Fatty Acid-binding Protein MRG J. Biol. Chem., November 21, 2003; 278(47): 47319 - 47325. [Abstract] [Full Text] [PDF]

				H. Huynh, P. K. H. Chow, L. L. P. Ooi, and K.-C. Soo A Possible Role for Insulin-like Growth Factor-binding Protein-3 Autocrine/Paracrine Loops in Controlling Hepatocellular Carcinoma Cell Proliferation Cell Growth Differ., March 1, 2002; 13(3): 115 - 122. [Abstract] [Full Text] [PDF]

				H. Huynh, C. Y. Ng, C. K. Ong, K. B. Lim, and T. W. M. Chan Cloning and Characterization of a Novel Pregnancy-Induced Growth Inhibitor in Mammary Gland Endocrinology, August 1, 2001; 142(8): 3607 - 3615. [Abstract] [Full Text] [PDF]

				I. E. Krop, D. Sgroi, D. A. Porter, K. L. Lunetta, R. LeVangie, P. Seth, C. M. Kaelin, E. Rhei, M. Bosenberg, S. Schnitt, et al. HIN-1, a putative cytokine highly expressed in normal but not cancerous mammary epithelial cells PNAS, July 24, 2001; (2001) 171138398. [Abstract] [Full Text] [PDF]

				R. Das, R. Hammamieh, R. Neill, M. Melhem, and M. Jett Expression Pattern of Fatty Acid-binding Proteins in Human Normal and Cancer Prostate Cells and Tissues Clin. Cancer Res., June 1, 2001; 7(6): 1706 - 1715. [Abstract] [Full Text] [PDF]

				D. Zohlnhofer, C. A. Klein, T. Richter, R. Brandl, A. Murr, T. Nuhrenberg, A. Schomig, P. A. Baeuerle, and F.-J. Neumann Gene Expression Profiling of Human Stent-Induced Neointima by cDNA Array Analysis of Microscopic Specimens Retrieved by Helix Cutter Atherectomy : Detection of FK506-Binding Protein 12 Upregulation Circulation, March 13, 2001; 103(10): 1396 - 1402. [Abstract] [Full Text] [PDF]

				M. Wang, Y. E. Liu, J. Ni, B. Aygun, I. D. Goldberg, and Y. E. Shi Induction of Mammary Differentiation by Mammary-derived Growth Inhibitor-related Gene That Interacts with an {{omega}}-3 Fatty Acid on Growth Inhibition of Breast Cancer Cells Cancer Res., November 1, 2000; 60(22): 6482 - 6487. [Abstract] [Full Text]

				R. J. Osborne and M. G. Hamshere A Genome-wide Map Showing Common Regions of Loss of Heterozygosity/Allelic Imbalance in Breast Cancer Cancer Res., July 1, 2000; 60(14): 3706 - 3712. [Abstract] [Full Text]

				A. T. Ferguson, E. Evron, C. B. Umbricht, T. K. Pandita, T. A. Chan, H. Hermeking, J. R. Marks, A. R. Lambers, P. A. Futreal, M. R. Stampfer, et al. High frequency of hypermethylation at the 14-3-3 sigma locus leads to gene silencing in breast cancer PNAS, May 23, 2000; 97(11): 6049 - 6054. [Abstract] [Full Text] [PDF]

				I. E. Krop, D. Sgroi, D. A. Porter, K. L. Lunetta, R. LeVangie, P. Seth, C. M. Kaelin, E. Rhei, M. Bosenberg, S. Schnitt, et al. HIN-1, a putative cytokine highly expressed in normal but not cancerous mammary epithelial cells PNAS, August 14, 2001; 98(17): 9796 - 9801. [Abstract] [Full Text] [PDF]