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

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 C Chang, Rachel Schiff and Xiao-Song Wang ()
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Jamunarani Veeraraghavan: Lester & Sue Smith Breast Center, Baylor College of Medicine
Ying Tan: Lester & Sue Smith Breast Center, Baylor College of Medicine
Xi-Xi Cao: Lester & Sue Smith Breast Center, Baylor College of Medicine
Jin Ah Kim: Lester & Sue Smith Breast Center, Baylor College of Medicine
Xian Wang: Lester & Sue Smith Breast Center, Baylor College of Medicine
Gary C Chamness: Lester & Sue Smith Breast Center, 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
Alejandro Contreras: Baylor College of Medicine
Susan G Hilsenbeck: Lester & Sue Smith Breast Center, Baylor College of Medicine
Eric C Chang: Lester & Sue Smith Breast Center, Baylor College of Medicine
Rachel Schiff: Lester & Sue Smith Breast Center, Baylor College of Medicine
Xiao-Song Wang: Lester & Sue Smith Breast Center, Baylor College of Medicine

Nature Communications, 2014, vol. 5, issue 1, 1-12

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms5577

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