Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Genomic amplification and oncogenic properties of the GASC1 histone demethylase gene in breast cancer

Oncogene volume 28, pages 4491–4500 (2009)Cite this article

Abstract

Earlier, mapping of the 9p23–24 amplicon in esophageal cancer cell lines led us to the positional cloning of gene amplified in squamous cell carcinoma 1 (GASC1), which encodes a nuclear protein with a Jumonji C domain that catalyzes lysine (K) demethylation of histones. However, the transforming roles of GASC1 in breast cancer remain to be determined. In this study, we identified GASC1 as one of the amplified genes for the 9p23–24 region in breast cancer, particularly in basal-like subtypes. The levels of GASC1 transcript expression were significantly higher in aggressive, basal-like breast cancers compared with nonbasal-like breast cancers. Our in vitro assays demonstrated that GASC1 induces transformed phenotypes, including growth factor-independent proliferation, anchorage-independent growth, altered morphogenesis in Matrigel, and mammosphere forming ability, when overexpressed in immortalized, nontransformed mammary epithelial MCF10A cells. Additionally, GASC1 demethylase activity regulates the expression of genes critical for stem cell self-renewal, including NOTCH1, and may be linked to the stem cell phenotypes in breast cancer. Thus, GASC1 is a driving oncogene in the 9p23–24 amplicon in human breast cancer and targeted inhibition of GASC1 histone demethylase in cancer could provide potential new avenues for therapeutic development.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

References

  • Bannister AJ, Schneider R, Myers FA, Thorne AW, Crane-Robinson C, Kouzarides T . (2005). Spatial distribution of di- and tri-methyl lysine 36 of histone H3 at active genes. J Biol Chem 280: 17732–17736.

    Article  CAS  Google Scholar 

  • Ben-Porath I, Thomson MW, Carey VJ, Ge R, Bell GW, Regev A et al. (2008). An embryonic stem cell-like gene expression signature in poorly differentiated aggressive human tumors. Nat Genet 40: 499–507.

    Article  CAS  Google Scholar 

  • Cloos PA, Christensen J, Agger K, Maiolica A, Rappsilber J, Antal T et al. (2006). The putative oncogene GASC1 demethylates tri- and dimethylated lysine 9 on histone H3. Nature 442: 307–311.

    Article  CAS  Google Scholar 

  • Debnath J, Muthuswamy SK, Brugge JS . (2003). Morphogenesis and oncogenesis of MCF-10A mammary epithelial acini grown in three-dimensional basement membrane cultures. Methods 30: 256–268.

    Article  CAS  Google Scholar 

  • Dontu G, Jackson KW, McNicholas E, Kawamura MJ, Abdallah WM, Wicha MS . (2004). Role of Notch signaling in cell-fate determination of human mammary stem/progenitor cells. Breast Cancer Res 6: R605–R615.

    Article  CAS  Google Scholar 

  • Esteller M . (2007). Cancer epigenomics: DNA methylomes and histone-modification maps. Nat Rev Genet 8: 286–298.

    Article  CAS  Google Scholar 

  • Farnie G, Clarke RB . (2007). Mammary stem cells and breast cancer—role of Notch signalling. Stem Cell Rev 3: 169–175.

    Article  CAS  Google Scholar 

  • Forozan F, Veldman R, Ammerman CA, Parsa NZ, Kallioniemi A, Kallioniemi OP et al. (1999). Molecular cytogenetic analysis of 11 new breast cancer cell lines. Br J Cancer 81: 1328–1334.

    Article  CAS  Google Scholar 

  • Geli J, Nord B, Frisk T, Edstrom Elder E, Ekstrom TJ, Carling T et al. (2005). Deletions and altered expression of the RIZ1 tumour suppressor gene in 1p36 in pheochromocytomas and abdominal paragangliomas. Int J Oncol 26: 1385–1391.

    CAS  PubMed  Google Scholar 

  • Han W, Jung EM, Cho J, Lee JW, Hwang KT, Yang SJ et al. (2008). DNA copy number alterations and expression of relevant genes in triple-negative breast cancer. Genes Chromosomes Cancer 47: 490–499.

    Article  CAS  Google Scholar 

  • Hess JL . (2004). MLL: a histone methyltransferase disrupted in leukemia. Trends Mol Med 10: 500–507.

    Article  CAS  Google Scholar 

  • Hu C, Dievart A, Lupien M, Calvo E, Tremblay G, Jolicoeur P . (2006). Overexpression of activated murine Notch1 and Notch3 in transgenic mice blocks mammary gland development and induces mammary tumors. Am J Pathol 168: 973–990.

    Article  CAS  Google Scholar 

  • Ignatoski KM, Lapointe AJ, Radany EH, Ethier SP . (1999). erbB-2 overexpression in human mammary epithelial cells confers growth factor independence. Endocrinology 140: 3615–3622.

    Article  CAS  Google Scholar 

  • Ignatoski KM, Maehama T, Markwart SM, Dixon JE, Livant DL, Ethier SP . (2000). ERBB-2 overexpression confers PI 3′ kinase-dependent invasion capacity on human mammary epithelial cells. Br J Cancer 82: 666–674.

    Article  CAS  Google Scholar 

  • Italiano A, Attias R, Aurias A, Perot G, Burel-Vandenbos F, Otto J et al. (2006). Molecular cytogenetic characterization of a metastatic lung sarcomatoid carcinoma: 9p23 neocentromere and 9p23-p24 amplification including JAK2 and JMJD2C. Cancer Genet Cytogenet 167: 122–130.

    Article  CAS  Google Scholar 

  • Jones PA, Baylin SB . (2007). The epigenomics of cancer. Cell 128: 683–692.

    Article  CAS  Google Scholar 

  • Katoh Y, Katoh M . (2007). Comparative integromics on JMJD2A, JMJD2B and JMJD2C: preferential expression of JMJD2C in undifferentiated ES cells. Int J Mol Med 20: 269–273.

    CAS  PubMed  Google Scholar 

  • Klose RJ, Kallin EM, Zhang Y . (2006). JmjC-domain-containing proteins and histone demethylation. Nat Rev Genet 7: 715–727.

    Article  CAS  Google Scholar 

  • Klose RJ, Zhang Y . (2007). Regulation of histone methylation by demethylimination and demethylation. Nat Rev Mol Cell Biol 8: 307–318.

    Article  CAS  Google Scholar 

  • Knuutila S, Bjorkqvist AM, Autio K, Tarkkanen M, Wolf M, Monni O et al. (1998). DNA copy number amplifications in human neoplasms: review of comparative genomic hybridization studies. Am J Pathol 152: 1107–1123.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kreike B, van Kouwenhove M, Horlings H, Weigelt B, Peterse H, Bartelink H et al. (2007). Gene expression profiling and histopathological characterization of triple-negative/basal-like breast carcinomas. Breast Cancer Res 9: R65.

    Article  Google Scholar 

  • Krivtsov AV, Armstrong SA . (2007). MLL translocations, histone modifications and leukaemia stem-cell development. Nat Rev Cancer 7: 823–833.

    Article  CAS  Google Scholar 

  • Krivtsov AV, Twomey D, Feng Z, Stubbs MC, Wang Y, Faber J et al. (2006). Transformation from committed progenitor to leukaemia stem cell initiated by MLL-AF9. Nature 442: 818–822.

    Article  CAS  Google Scholar 

  • Lal G, Padmanabha L, Smith BJ, Nicholson RM, Howe JR, O'Dorisio MS et al. (2006). RIZ1 is epigenetically inactivated by promoter hypermethylation in thyroid carcinoma. Cancer 107: 2752–2759.

    Article  CAS  Google Scholar 

  • Loh YH, Zhang W, Chen X, George J, Ng HH . (2007). Jmjd1a and Jmjd2c histone H3 Lys 9 demethylases regulate self-renewal in embryonic stem cells. Genes Dev 21: 2545–2557.

    Article  CAS  Google Scholar 

  • Moffa AB, Tannheimer SL, Ethier SP . (2004). Transforming potential of alternatively spliced variants of fibroblast growth factor receptor 2 in human mammary epithelial cells. Mol Cancer Res 2: 643–652.

    CAS  PubMed  Google Scholar 

  • Neve RM, Chin K, Fridlyand J, Yeh J, Baehner FL, Fevr T et al. (2006). A collection of breast cancer cell lines for the study of functionally distinct cancer subtypes. Cancer Cell 10: 515–527.

    Article  CAS  Google Scholar 

  • Northcott PA, Nakahara Y, Wu X, Feuk L, Ellison DW, Croul S et al. (2009). Multiple recurrent genetic events converge on control of histone lysine methylation in medulloblastoma. Nat Genet 41: 465–472.

    Article  CAS  Google Scholar 

  • Peters AH, O'Carroll D, Scherthan H, Mechtler K, Sauer S, Schofer C et al. (2001). Loss of the Suv39 h histone methyltransferases impairs mammalian heterochromatin and genome stability. Cell 107: 323–337.

    Article  CAS  Google Scholar 

  • Pierga JY, Reis-Filho JS, Cleator SJ, Dexter T, Mackay A, Simpson P et al. (2007). Microarray-based comparative genomic hybridisation of breast cancer patients receiving neoadjuvant chemotherapy. Br J Cancer 96: 341–351.

    Article  CAS  Google Scholar 

  • Poetsch M, Dittberner T, Woenckhaus C . (2002). Frameshift mutations of RIZ, but no point mutations in RIZ1 exons in malignant melanomas with deletions in 1p36. Oncogene 21: 3038–3042.

    Article  CAS  Google Scholar 

  • Politi K, Feirt N, Kitajewski J . (2004). Notch in mammary gland development and breast cancer. Semin Cancer Biol 14: 341–347.

    Article  CAS  Google Scholar 

  • Rizzo P, Osipo C, Foreman K, Golde T, Osborne B, Miele L . (2008). Rational targeting of Notch signaling in cancer. Oncogene 27: 5124–5131.

    Article  CAS  Google Scholar 

  • Sansone P, Storci G, Giovannini C, Pandolfi S, Pianetti S, Taffurelli M et al. (2007). p66Shc/Notch-3 interplay controls self-renewal and hypoxia survival in human stem/progenitor cells of the mammary gland expanded in vitro as mammospheres. Stem Cells 25: 807–815.

    Article  CAS  Google Scholar 

  • Savelyeva L, Claas A, An H, Weber RG, Lichter P, Schwab M . (1999). Retention of polysomy at 9p23-24 during karyotypic evolution in human breast cancer cell line COLO 824. Genes Chromosomes Cancer 24: 87–93.

    Article  CAS  Google Scholar 

  • Savelyeva L, Claas A, Matzner I, Schlag P, Hofmann W, Scherneck S et al. (2001). Constitutional genomic instability with inversions, duplications, and amplifications in 9p23-24 in BRCA2 mutation carriers. Cancer Res 61: 5179–5185.

    CAS  PubMed  Google Scholar 

  • Sharpless NE . (2005). INK4a/ARF: a multifunctional tumor suppressor locus. Mutat Res 576: 22–38.

    Article  CAS  Google Scholar 

  • Shi Y, Whetstine JR . (2007). Dynamic regulation of histone lysine methylation by demethylases. Mol Cell 25: 1–14.

    Article  CAS  Google Scholar 

  • Steele-Perkins G, Fang W, Yang XH, Van Gele M, Carling T, Gu J et al. (2001). Tumor formation and inactivation of RIZ1, an Rb-binding member of a nuclear protein-methyltransferase superfamily. Genes Dev 15: 2250–2262.

    Article  CAS  Google Scholar 

  • Vinatzer U, Gollinger M, Mullauer L, Raderer M, Chott A, Streubel B . (2008). Mucosa-associated lymphoid tissue lymphoma: novel translocations including rearrangements of ODZ2, JMJD2C, and CNN3. Clin Cancer Res 14: 6426–6431.

    Article  CAS  Google Scholar 

  • Wang GG, Cai L, Pasillas MP, Kamps MP . (2007). NUP98-NSD1 links H3K36 methylation to Hox-A gene activation and leukaemogenesis. Nat Cell Biol 9: 804–812.

    Article  CAS  Google Scholar 

  • Whetstine JR, Nottke A, Lan F, Huarte M, Smolikov S, Chen Z et al. (2006). Reversal of histone lysine trimethylation by the JMJD2 family of histone demethylases. Cell 125: 467–481.

    Article  CAS  Google Scholar 

  • Wissmann M, Yin N, Muller JM, Greschik H, Fodor BD, Jenuwein T et al. (2007). Cooperative demethylation by JMJD2C and LSD1 promotes androgen receptor-dependent gene expression. Nat Cell Biol 9: 347–353.

    Article  CAS  Google Scholar 

  • Woods Ignatoski KM, Livant DL, Markwart S, Grewal NK, Ethier SP . (2003). The role of phosphatidylinositol 3′-kinase and its downstream signals in erbB-2-mediated transformation. Mol Cancer Res 1: 551–560.

    CAS  PubMed  Google Scholar 

  • Yang ZQ, Imoto I, Fukuda Y, Pimkhaokham A, Shimada Y, Imamura M et al. (2000). Identification of a novel gene, GASC1, within an amplicon at 9p23-24 frequently detected in esophageal cancer cell lines. Cancer Res 60: 4735–4739.

    CAS  PubMed  Google Scholar 

  • Yang ZQ, Imoto I, Pimkhaokham A, Shimada Y, Sasaki K, Oka M et al. (2001). A novel amplicon at 9p23–24 in squamous cell carcinoma of the esophagus that lies proximal to GASC1 and harbors NFIB. Jpn J Cancer Res 92: 423–428.

    Article  CAS  Google Scholar 

  • Yang ZQ, Streicher KL, Ray ME, Abrams J, Ethier SP . (2006). Multiple interacting oncogenes on the 8p11-p12 amplicon in human breast cancer. Cancer Res 66: 11632–11643.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by a grant from the Department of Defense Breast Cancer Program (DAMD17–03–1–0459) to Zeng-Quan Yang and a grant from the National Institutes of Health (RO1 CA100724) to Stephen P Ethier.

Author information

Authors and Affiliations

  1. Department of Pathology, Breast Cancer Program, Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA

    G Liu, A Bollig-Fischer, S P Ethier & Z -Q Yang

  2. Division of Radiation Oncology and Experimental Therapy, Netherlands Cancer Institute, Amsterdam, The Netherlands

    B Kreike

  3. Department of Pathology, Academic Medical Center, Amsterdam, The Netherlands

    M J van de Vijver

  4. Department of Internal Medicine, Biostatistics Core, Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA

    J Abrams

Authors
  1. G Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A Bollig-Fischer
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. B Kreike
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M J van de Vijver
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. J Abrams
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. S P Ethier
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Z -Q Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Z -Q Yang.

Additional information

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

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Liu, G., Bollig-Fischer, A., Kreike, B. et al. Genomic amplification and oncogenic properties of the GASC1 histone demethylase gene in breast cancer. Oncogene 28, 4491–4500 (2009). https://doi.org/10.1038/onc.2009.297

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2009.297

Keywords

This article is cited by

Search

Advanced search

Quick links