Recurrent ESR1CCDC170 rearrangements in an aggressive subset of oestrogen receptor-positive breast cancers


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 ESR1CCDC170-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 ESR1CCDC170 fusions in a more aggressive subset of ER+ breast cancer, which suggests a new concept of ER pathobiology in breast cancer.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Discovering recurrent gene fusions in invasive breast cancer.
Figure 2: Characterization of the ESR1CCDC170 fusion in breast cancer cell lines and tissues.
Figure 3: Characterization of ESR1–CCDC170 protein products and their transforming activity in MCF10A breast epithelial cells.
Figure 4: ESR1CCDC170 endows more aggressive phenotypes in T47D ER+ breast cancer cells.
Figure 5: Evaluating the function of the endogenous ESR1CCDC170 fusion in HCC1428 breast cancer cells by genetic inhibition.
Figure 6: ESR1CCDC170 may engage Gab1 to enhance cell motility and augment growth factor signalling.


  1. 1

    Tomlins, S. A. et al. Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Science 310, 644–648 (2005).

  2. 2

    Soda, M. et al. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature 448, 561–566 (2007).

  3. 3

    Koivunen, J. P. et al. EML4-ALK fusion gene and efficacy of an ALK kinase inhibitor in lung cancer. Clin. Cancer Res. 14, 4275–4283 (2008).

  4. 4

    Bass, A.J. et al. Genomic sequencing of colorectal adenocarcinomas identifies a recurrent VTI1A-TCF7L2 fusion. Nat. Genet. 43, 964–968 (2011).

  5. 5

    Pierron, G. et al. A new subtype of bone sarcoma defined by BCOR-CCNB3 gene fusion. Nat. Genet. 44, 461–466 (2012).

  6. 6

    Singh, D. et al. Transforming fusions of FGFR and TACC genes in human glioblastoma. Science 337, 1231–1235 (2012).

  7. 7

    Robinson, D. R. et al. Functionally recurrent rearrangements of the MAST kinase and Notch gene families in breast cancer. Nat. Med. 17, 1646–1651 (2011).

  8. 8

    Banerji, S. et al. Sequence analysis of mutations and translocations across breast cancer subtypes. Nature 486, 405–409 (2012).

  9. 9

    Sotiriou, C. et al. Breast cancer classification and prognosis based on gene expression profiles from a population-based study. Proc. Natl Acad. Sci. USA 100, 10393–10398 (2003).

  10. 10

    Wang, X. S. et al. An integrative approach to reveal driver gene fusions from paired-end sequencing data in cancer. Nat. Biotechnol. 27, 1005–1011 (2009).

  11. 11

    Parra, G. et al. Tandem chimerism as a means to increase protein complexity in the human genome. Genome Res. 16, 37–44 (2006).

  12. 12

    Akiva, P. et al. Transcription-mediated gene fusion in the human genome. Genome Res. 16, 30–36 (2006).

  13. 13

    Geiss, G. K. et al. Direct multiplexed measurement of gene expression with color-coded probe pairs. Nat. Biotechnol. 26, 317–325 (2008).

  14. 14

    Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumours. Nature 490, 61–70 (2012).

  15. 15

    Dunbier, A. K. et al. ESR1 is co-expressed with closely adjacent uncharacterised genes spanning a breast cancer susceptibility locus at 6q25.1. PLoS Genetics 7, e1001382 (2011).

  16. 16

    Cheang, M. C. et al. Ki67 index, HER2 status, and prognosis of patients with luminal B breast cancer. J. Natl Cancer Inst. 101, 736–750 (2009).

  17. 17

    Voduc, K. D. et al. Breast cancer subtypes and the risk of local and regional relapse. J. Clin. Oncol. 28, 1684–1691 (2010).

  18. 18

    Tran, B. & Bedard, P. L. Luminal-B breast cancer and novel therapeutic targets. Breast Cancer Res. 13, 221 (2011).

  19. 19

    Dickson, R. B., Bates, S. E., McManaway, M. E. & Lippman, M. E. Characterization of estrogen responsive transforming activity in human breast cancer cell lines. Cancer Res. 46, 1707–1713 (1986).

  20. 20

    Gu, H. & Neel, B. G. The "Gab" in signal transduction. Trends Cell Biol. 13, 122–130 (2003).

  21. 21

    Liu, Y. & Rohrschneider, L. R. The gift of Gab. FEBS Lett. 515, 1–7 (2002).

  22. 22

    Rajadurai, C. V. et al. Met receptor tyrosine kinase signals through a cortactin-Gab1 scaffold complex, to mediate invadopodia. J. Cell Sci. 125, 2940–2953 (2012).

  23. 23

    Shou, J. et al. Mechanisms of tamoxifen resistance: increased estrogen receptor-HER2/neu cross-talk in ER/HER2-positive breast cancer. J. Natl Cancer Inst. 96, 926–935 (2004).

  24. 24

    de Leeuw, R., Neefjes, J. & Michalides, R. A role for estrogen receptor phosphorylation in the resistance to tamoxifen. Int. J. Breast Cancer 2011, 232435 (2011).

  25. 25

    Jin, Z. G., Wong, C., Wu, J. & Berk, B. C. Flow shear stress stimulates Gab1 tyrosine phosphorylation to mediate protein kinase B and endothelial nitric-oxide synthase activation in endothelial cells. J. Biol. Chem. 280, 12305–12309 (2005).

  26. 26

    Campbell, R. A. et al. Phosphatidylinositol 3-kinase/AKT-mediated activation of estrogen receptor alpha: a new model for anti-estrogen resistance. J. Biol. Chem. 276, 9817–9824 (2001).

  27. 27

    Sakarya, O. et al. RNA-Seq mapping and detection of gene fusions with a suffix array algorithm. PLoS Comput. Biol. 8, e1002464 (2012).

  28. 28

    Rodrigues, G. A., Falasca, M., Zhang, Z., Ong, S. H. & Schlessinger, J. A novel positive feedback loop mediated by the docking protein Gab1 and phosphatidylinositol 3-kinase in epidermal growth factor receptor signaling. Mol. Cell. Biol. 20, 1448–1459 (2000).

  29. 29

    Gingeras, T. R. Implications of chimaeric non-co-linear transcripts. Nature 461, 206–211 (2009).

  30. 30

    Martelli, M. P. et al. EML4-ALK rearrangement in non-small cell lung cancer and non-tumor lung tissues. Am. J. Pathol. 174, 661–670 (2009).

  31. 31

    Maes, B. et al. The NPM-ALK and the ATIC-ALK fusion genes can be detected in non-neoplastic cells. Am. J. Pathol. 158, 2185–2193 (2001).

  32. 32

    Li, H., Wang, J., Mor, G. & Sklar, J. A neoplastic gene fusion mimics trans-splicing of RNAs in normal human cells. Science 321, 1357–1361 (2008).

  33. 33

    Biernaux, C., Loos, M., Sels, A., Huez, G. & Stryckmans, P. Detection of major bcr-abl gene expression at a very low level in blood cells of some healthy individuals. Blood 86, 3118–3122 (1995).

  34. 34

    Jones, D. T. et al. Tandem duplication producing a novel oncogenic BRAF fusion gene defines the majority of pilocytic astrocytomas. Cancer Res. 68, 8673–8677 (2008).

  35. 35

    Lipson, D. et al. Identification of new ALK and RET gene fusions from colorectal and lung cancer biopsies. Nat. Med. 18, 382–384 (2012).

  36. 36

    Ng, C. K. et al. The role of tandem duplicator phenotype in tumour evolution in high-grade serous ovarian cancer. J. Pathol. 226, 703–712 (2012).

  37. 37

    Varela, I. et al. Somatic structural rearrangements in genetically engineered mouse mammary tumors. Genome Biol. 11, R100 (2010).

  38. 38

    McPherson, A. et al. deFuse: an algorithm for gene fusion discovery in tumor RNA-Seq data. PLoS Comput. Biol. 7, e1001138 (2011).

  39. 39

    Maher, C. A. et al. Chimeric transcript discovery by paired-end transcriptome sequencing. Proc. Natl Acad. Sci. USA 106, 12353–12358 (2009).

  40. 40

    Trapnell, C., Pachter, L. & Salzberg, S.L. TopHat: discovering splice junctions with RNA-Seq. Bioinformatics 25, 1105–1111 (2009).

  41. 41

    Hahn, Y. et al. Finding fusion genes resulting from chromosome rearrangement by analyzing the expressed sequence databases. Proc. Natl Acad. Sci. USA 101, 13257–13261 (2004).

  42. 42

    Olshen, A. B., Venkatraman, E. S., Lucito, R. & Wigler, M. Circular binary segmentation for the analysis of array-based DNA copy number data. Biostatistics 5, 557–572 (2004).

  43. 43

    Thorvaldsdottir, H., Robinson, J. T. & Mesirov, J. P. Integrative Genomics Viewer (IGV): high-performance genomics data visualization and exploration. Brief Bioinform. 14, 178–192 (2013).

  44. 44

    Heiser, L. M. et al. Subtype and pathway specific responses to anticancer compounds in breast cancer. Proc. Natl Acad. Sci. USA 109, 2724–2729 (2012).

  45. 45

    Koboldt, D.C. et al. Comprehensive molecular portraits of human breast tumours. Nature 490, 61–70 (2012).

  46. 46

    Zhu, J. et al. The UCSC Cancer Genomics Browser. Nat. Methods 6, 239–240 (2009).

  47. 47

    Tham, Y. L. et al. Clinical response to neoadjuvant docetaxel predicts improved outcome in patients with large locally advanced breast cancers. Breast Cancer Res. Treat. 94, 279–284 (2005).

  48. 48

    Dowsett, M. et al. Assessment of Ki67 in breast cancer: recommendations from the International Ki67 in Breast Cancer working group. J. Natl Cancer Inst. 103, 1656–1664 (2011).

  49. 49

    Itamochi, H. et al. Checkpoint kinase inhibitor AZD7762 overcomes cisplatin resistance in clear cell carcinoma of the ovary. Int. J. Gynecol. Cancer 24, 61–69 (2014).

Download references


The results published here are in part based on data generated by TCGA (dbGaP accession: phs000178.v6.p6). We thank Dr Joe W. Gray for providing the genomic data for breast cancer cell lines. We thank Zhongqiu Guo and Sufeng Mao for help with Ki67 IHC assays, Sabrina Herrera for help with pathology analysis, and the Antibody-based Proteomics Core of the Dan L. Duncan Cancer Center (DLDCC) at BCM (supported by NCI P30-125123) for help with cell line extracts. The computational infrastructure was supported by the DLDCC Biostatistics and Informatics Shared Resource and the Rice University BlueBioU Computer Cluster (supported by a 2010 IBM Award and NIH grant NCRR S10RR02950). This study was supported by CDMRP grants W81XWH-12-1-0166 (X.-S.W.), W81XWH-12-1-0167 (R.S.), W81XWH-13-1-0201 (X.-X.C) and W81XWH-13-1-0431 (J.V.), Nancy Owens Memorial foundation (X.-S.W.), Susan G. Komen Foundation PDF12231561 (J.A.K.), and PG12221410 (X.-S.W., R.S., S.G.H.). NIH grant CA183976 (X.-S.W.), P30-125123-06 (S.G.H.), and CPRIT grant RP130135 (E.C.C.). All breast tumour tissues were provided by the Tumor Bank of the BCM Breast Center.

Author information

X.-S.W. conceived and supervised the study, performed bioinformatics analysis, analysed the data and wrote the manuscript. J.V. designed and performed cell biology, mechanistic and in vivo experiments, analysed the data and co-wrote the manuscript. Y.T. designed and performed molecular biology experiments, analysed the data and co-wrote the manuscript. X.-X.C. performed cell biology experiments and pathology studies. J.A.K. helped develop stable overexpression cell lines. X.W. assisted in the in vivo studies. S.N.M. and L.J.N.C. helped perform Nanostring assay. D.P.E. provided breast cancer cell lines and RNA extracts. A.C. helped with pathology studies. S.G.H performed the statistical analysis. G.C.C. edited the manuscript. R.S. and E.C.C. advised on the study and revised the manuscript.

Correspondence to Xiao-Song Wang.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Figures and Tables

Supplementary Figures 1-12 and Supplementary Tables 1-3 (PDF 1052 kb)

Supplementary Data 1

380 recurrent fusion candidates associated with recurring somatic unbalanced breakpoints computed based on copy number data. Note: , 5' and 3' genes locate at the same strand with 5' gene placed upstream of 3' gene; 5' and 3' genes locate at the same strand but 3' gene is placed upstream of 5' gene; <> 5' and 3' genes are in different strand. AdjN, paired adjacent normal breast tissues. The number of tumor or blood samples harboring meaningful copy number breakpoints in 5' or 3' partner genes are shown in the last column. 5'break, 5'partner gene has copy number breakpoint resulting in 5' amplification or 3' deletion of the gene. 3'break, 3'partner gene has copy number breakpoint resulting in 5' deletion or 3' amplification of the gene. Note, there is slight difference in the incidence of ESR1-CCDC170 and associated copy number breakpoints computed by the Fusion Zoom pipeline and that of final results curated based on newer release of TCGA data. Also not all ESR1/CCDC170 breakpoint positive cases are identified as ESR1-CCDC170 positive by RNAseq data analysis. (XLS 129 kb)

Supplementary Data 2

Reconstructed putative fusion-variant sequences by randomly combining each of ESR1 exons with each of the CCDC170 exons. (TXT 4017 kb)

Supplementary Data 3

The sequences of ESR1-CCDC170 chimerical mate-pair reads detected from TCGA breast tumors and the manual curation results. (XLS 143 kb)

Supplementary Data 4

ESR1-CCDC170 genomic fusion sequences of fusion-positive breast cancer cell lines and tumors identified by genomic PCR and capillary sequencing. (TXT 5 kb)

Supplementary Data 5

The predicted open-reading frame sequences of ESR1-CCDC170 fusion variant E2-E6, E2-E7, E2-E8, and E2-E10. (TXT 3 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Veeraraghavan, J., Tan, Y., Cao, X. et al. Recurrent ESR1CCDC170 rearrangements in an aggressive subset of oestrogen receptor-positive breast cancers. Nat Commun 5, 4577 (2014).

Download citation

Further reading


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.