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LARG at chromosome 11q23 has functional characteristics of a tumor suppressor in human breast and colorectal cancer

Oncogene volume 28, pages 4189–4200 (2009)Cite this article

Abstract

Deletion of 11q23–q24 is frequent in a diverse variety of malignancies, including breast and colorectal carcinoma, implicating the presence of a tumor suppressor gene at that chromosomal region. We examined a 6-Mb region on 11q23 by high-resolution deletion mapping, using both loss of heterozygosity analysis and customized microarray comparative genomic hybridization. LARG (leukemia-associated Rho guanine-nucleotide exchange factor) (also called ARHGEF12), identified from the analysed region, is frequently underexpressed in breast and colorectal carcinomas with a reduced expression observed in all breast cancer cell lines (n=11), in 12 of 38 (32%) primary breast cancers, 5 of 10 (50%) colorectal cell lines and in 20 of 37 (54%) primary colorectal cancers. Underexpression of the LARG transcript was significantly associated with genomic loss (P=0.00334). Hypermethylation of the LARG promoter was not detected in either breast or colorectal cancer, and treatment of four breast and four colorectal cancer cell lines with 5-aza-2′-deoxycytidine and/or trichostatin A did not result in a reactivation of LARG. Enforced expression of LARG in breast and colorectal cancer cells by stable transfection resulted in reduced cell proliferation and colony formation, as well as in a markedly slower cell migration rate in colorectal cancer cells, providing functional evidence for LARG as a candidate tumor suppressor gene.

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Acknowledgements

We thank Dr Glenn Koh for assistance with review of case notes; YC Seo, Angela Chang, S Tohari, Irene HK Lim and Gan Yar Chze for excellent technical assistance; and Dr Eric Yap for helpful discussions. This study was supported by Grants from the National Medical Research Council (NMRC) of Singapore (NMRC/0076/1995, NMRC/0440/2000, NMRC/0570/2001, NMRC/0843/2004); SingHealth Foundation (SHF/FG235P/2005); the Singapore Cancer Society, SGH Research Fund, Cancer Research Education Fund, NCC and Department of Clinical Research, SGH, to AL. We gratefully acknowledge the grant support from the US Department of Energy under Contract No. DE-AC02-05CH11231, USAMRMC BC 061995; National Institutes of Health, National Cancer Institute (P50 CA 58207, P50 CA 83639, P30 CA 82103, U54 CA 112970, U24 CA 126477 P01 CA 64602); National Human Genome Research Institute (U24 CA 126551) and SmithKline Beecham Corporation, to JWG.

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Author notes

  1. C Rudduck

    Present address: 8Current address: Childrens’ Hospital at Westmead, Sydney, New South Wales 2145, Australia,

  2. G S Hong

    Present address: 9Current address: GS Hong Surgical Care, Mt Elizabeth Medical Centre, Singapore 228510,

Authors and Affiliations

  1. Division of Medical Sciences, National Cancer Centre, Singapore

    D C T Ong, Y M Ho, D K H Lie, C L M Chua & A S G Lee

  2. Department of Pathology, Singapore General Hospital, Singapore

    C Rudduck & P H Tan

  3. UCSF Comprehensive Cancer Center, University of California, San Francisco, CA, USA

    K Chin, W -L Kuo & J W Gray

  4. Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA

    W -L Kuo & J W Gray

  5. Department of Colorectal Surgery, Singapore General Hospital, Singapore

    K W Eu & F Seow-Choen

  6. Department of General Surgery, Singapore General Hospital, Singapore

    C Y Wong & G S Hong

  7. Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore

    A S G Lee

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Correspondence to A S G Lee.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Ong, D., Ho, Y., Rudduck, C. et al. LARG at chromosome 11q23 has functional characteristics of a tumor suppressor in human breast and colorectal cancer. Oncogene 28, 4189–4200 (2009). https://doi.org/10.1038/onc.2009.266

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