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Frequent copy number gains at 1q21 and 1q32 are associated with overexpression of the ETS transcription factors ETV3 and ELF3 in breast cancer irrespective of molecular subtypes

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Abstract

Several ETS transcription factors are involved in the pathogenesis of human cancers by different mechanisms. As gene copy number gain/amplification is an alternative mechanism of oncogenic activation and 1q gain is the most common copy number change in breast carcinoma, we investigated how that genomic change impacts in the expression of the three 1q ETS family members ETV3, ELK4, and ELF3. We have first evaluated 141 breast carcinomas for genome-wide copy number changes by chromosomal CGH and showed that 1q21 and 1q32 were the two chromosome bands with most frequent genomic copy number gains. Second, we confirmed by FISH with locus-specific BAC clones that cases showing 1q gain/amplification by CGH showed copy number increase of the ETS genes ETV3 (located in 1q21~23), ELF3, and ELK4 (both in 1q32). Third, gene expression levels of the three 1q ETS genes, as well as their potential targets MYC and CRISP3, were evaluated by quantitative real-time PCR. We here show for the first time that the most common genomic copy number gains in breast cancer, 1q21 and 1q32, are associated with overexpression of the ETS transcription factors ETV3 and ELF3 (but not ELK4) at these loci irrespective of molecular subtypes. Among the three 1q ETS genes, ELF3 has a relevant role in breast carcinogenesis and is also the most likely target of the 1q copy number increase. The basal-like molecular subtype presented the worst prognosis regarding disease-specific survival, but no additional prognostic value was found for 1q copy number status or ELF3 expression. In addition, we show that there is a correlation between the expression of the oncogene MYC, irrespectively of copy number gain at its loci in 8q24, and the expression of both the transcriptional repressor ETV3 and the androgen respondent ELK4.

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Acknowledgments

This study was supported by Fundação para a Ciência e Tecnologia (FCT; PEST-OE/SAL/UI0776/2011) and by Liga Portuguesa Contra o Cancro, Núcleo Regional do Norte. Bárbara Mesquita (SFRH/BD/30097/2006) is a research fellow funded by FCT. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Genetics, Portuguese Oncology Institute, Rua Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal

    Bárbara Mesquita, Carmen Jerónimo & Manuel R. Teixeira

  2. Department of Pathology, Portuguese Oncology Institute, Porto, Portugal

    Paula Lopes, Mariana Afonso, Conceição Leal & Rui Henrique

  3. Department of Medical Oncology, Portuguese Oncology Institute, Porto, Portugal

    Ana Rodrigues & Deolinda Pereira

  4. Cancer Genetics Group, Research Centre of the Portuguese Oncology Institute, Porto, Portugal

    Bárbara Mesquita & Manuel R. Teixeira

  5. Cancer Epigenetics Group, Research Centre of the Portuguese Oncology Institute, Porto, Portugal

    Rui Henrique & Carmen Jerónimo

  6. Department of Pathology and Molecular Immunology, Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Porto, Portugal

    Rui Henrique, Carmen Jerónimo & Manuel R. Teixeira

  7. Department of Cancer Prevention, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway

    Guro E. Lind & Ragnhild A. Lothe

  8. Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Oslo, Norway

    Guro E. Lind, Ragnhild A. Lothe & Manuel R. Teixeira

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  1. Bárbara Mesquita
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  2. Paula Lopes
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  3. Ana Rodrigues
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  4. Deolinda Pereira
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  5. Mariana Afonso
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  6. Conceição Leal
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  9. Carmen Jerónimo
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  10. Ragnhild A. Lothe
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  11. Manuel R. Teixeira
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Correspondence to Manuel R. Teixeira.

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Mesquita, B., Lopes, P., Rodrigues, A. et al. Frequent copy number gains at 1q21 and 1q32 are associated with overexpression of the ETS transcription factors ETV3 and ELF3 in breast cancer irrespective of molecular subtypes. Breast Cancer Res Treat 138, 37–45 (2013). https://doi.org/10.1007/s10549-013-2408-2

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