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Recurrent ESR1–CCDC170 rearrangements in an aggressive subset of oestrogen receptor-positive breast cancers

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  • Jamunarani Veeraraghavan

    (Lester & Sue Smith Breast Center, Baylor College of Medicine
    Dan L. Duncan Cancer Center, Baylor College of Medicine
    Baylor College of Medicine)

  • Ying Tan

    (Lester & Sue Smith Breast Center, Baylor College of Medicine
    Dan L. Duncan Cancer Center, Baylor College of Medicine
    Baylor College of Medicine)

  • Xi-Xi Cao

    (Lester & Sue Smith Breast Center, Baylor College of Medicine
    Dan L. Duncan Cancer Center, Baylor College of Medicine
    Baylor College of Medicine)

  • Jin Ah Kim

    (Lester & Sue Smith Breast Center, Baylor College of Medicine
    Dan L. Duncan Cancer Center, Baylor College of Medicine
    Baylor College of Medicine)

  • Xian Wang

    (Lester & Sue Smith Breast Center, Baylor College of Medicine
    Dan L. Duncan Cancer Center, Baylor College of Medicine
    Baylor College of Medicine)

  • Gary C Chamness

    (Lester & Sue Smith Breast Center, Baylor College of Medicine
    Dan L. Duncan Cancer Center, Baylor College of Medicine
    Baylor College of Medicine)

  • Sourindra N Maiti

    (The University of Texas MD Anderson Cancer Center)

  • Laurence J N Cooper

    (The University of Texas MD Anderson Cancer Center)

  • Dean P Edwards

    (Baylor College of Medicine
    Baylor College of Medicine)

  • Alejandro Contreras

    (Baylor College of Medicine)

  • Susan G Hilsenbeck

    (Lester & Sue Smith Breast Center, Baylor College of Medicine
    Dan L. Duncan Cancer Center, Baylor College of Medicine
    Baylor College of Medicine)

  • Eric C Chang

    (Lester & Sue Smith Breast Center, Baylor College of Medicine
    Dan L. Duncan Cancer Center, Baylor College of Medicine
    Baylor College of Medicine)

  • Rachel Schiff

    (Lester & Sue Smith Breast Center, Baylor College of Medicine
    Dan L. Duncan Cancer Center, Baylor College of Medicine
    Baylor College of Medicine
    Baylor College of Medicine)

  • Xiao-Song Wang

    (Lester & Sue Smith Breast Center, Baylor College of Medicine
    Dan L. Duncan Cancer Center, Baylor College of Medicine
    Baylor College of Medicine
    Baylor College of Medicine)

Abstract

Characterizing the genetic alterations leading to the more aggressive forms of oestrogen receptor-positive (ER+) breast cancers is of critical significance in breast cancer management. Here we identify recurrent rearrangements between the oestrogen receptor gene ESR1 and its neighbour CCDC170, which are enriched in the more aggressive and endocrine-resistant luminal B tumours, through large-scale analyses of breast cancer transcriptome and copy number alterations. Further screening of 200 ER+ breast cancers identifies eight ESR1–CCDC170-positive tumours. These fusions encode amino-terminally truncated CCDC170 proteins (ΔCCDC170). When introduced into ER+ breast cancer cells, ΔCCDC170 leads to markedly increased cell motility and anchorage-independent growth, reduced endocrine sensitivity and enhanced xenograft tumour formation. Mechanistic studies suggest that ΔCCDC170 engages Gab1 signalosome to potentiate growth factor signalling and enhance cell motility. Together, this study identifies neoplastic ESR1–CCDC170 fusions in a more aggressive subset of ER+ breast cancer, which suggests a new concept of ER pathobiology in breast cancer.

Suggested Citation

  • Jamunarani Veeraraghavan & Ying Tan & Xi-Xi Cao & Jin Ah Kim & Xian Wang & Gary C Chamness & Sourindra N Maiti & Laurence J N Cooper & Dean P Edwards & Alejandro Contreras & Susan G Hilsenbeck & Eric , 2014. "Recurrent ESR1–CCDC170 rearrangements in an aggressive subset of oestrogen receptor-positive breast cancers," Nature Communications, Nature, vol. 5(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms5577
    DOI: 10.1038/ncomms5577
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    Cited by:

    1. Fengju Chen & Yiqun Zhang & Darshan S. Chandrashekar & Sooryanarayana Varambally & Chad J. Creighton, 2023. "Global impact of somatic structural variation on the cancer proteome," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    2. Kadir Buyukcelebi & Alexander J. Duval & Fatih Abdula & Hoda Elkafas & Fidan Seker-Polat & Mazhar Adli, 2024. "Integrating leiomyoma genetics, epigenomics, and single-cell transcriptomics reveals causal genetic variants, genes, and cell types," Nature Communications, Nature, vol. 15(1), pages 1-14, December.

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