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Estrogen receptor alpha (ESR1) gene amplification is frequent in breast cancer

Abstract

Using an Affymetrix 10K SNP array to screen for gene copy number changes in breast cancer, we detected a single-gene amplification of the ESR1 gene, which encodes estrogen receptor alpha, at 6q25. A subsequent tissue microarray analysis of more than 2,000 clinical breast cancer samples showed ESR1 amplification in 20.6% of breast cancers. Ninety-nine percent of tumors with ESR1 amplification showed estrogen receptor protein overexpression, compared with 66.6% cancers without ESR1 amplification (P < 0.0001). In 175 women who had received adjuvant tamoxifen monotherapy, survival was significantly longer for women with cancer with ESR1 amplification than for women with estrogen receptor–expressing cancers without ESR1 amplification (P = 0.023). Notably, we also found ESR1 amplification in benign and precancerous breast diseases, suggesting that ESR1 amplification may be a common mechanism in proliferative breast disease and a very early genetic alteration in a large subset of breast cancers.

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Figure 1: qPCR-based determination of ESR1 gene copy numbers in tumors with ESR1 amplification ('Amp #1' through 'Amp #4') and without amplification ('Norm #1' through 'Norm #4') selected according to FISH analysis.
Figure 2: Impact of ESR1 amplification (defined as an ESR1/centromere 6 copy number ratio ≥2.0) and expression on prognosis in affected individuals who received tamoxifen monotherapy.
Figure 3: Size and position of the ESR1 amplicon in 24 breast cancer samples.

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Acknowledgements

We thank the University Medical Center Hamburg Eppendorf for providing an outstanding environment for research. We are grateful to S. Schnöger, A. Blaszczyk-Wewer, G. Rieck, M. Sachs, S. Schmidt, M. Härtling and M. Mirlacher for technical support.

Author information

Authors and Affiliations

Authors

Contributions

F.H., P.R.S. and C.R. produced the ESR1 FISH probes, performed FISH analysis and contributed to the writing of the paper; Z.J. contributed to FISH analysis; M.W. and F.H. performed amplicon mapping; F.H. and O.H. performed qPCR analysis; A.L. and L.T. performed estrogen receptor immunohistochemistry analysis; F.J. contributed to data analysis and interpretation; K.A.-K. and G.S. selected tissues and performed histological diagnosis and R.S. and G.S. designed the study and contributed to the writing of the paper.

Corresponding author

Correspondence to Ronald Simon.

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Competing interests

The University Medical Center Hamburg-Eppendorf has filed a patent application for certain technology described in the paper.

Supplementary information

Supplementary Table 1

Prevalence of coamplifications involving ESR1 in breast cancer. (PDF 46 kb)

Supplementary Table 2

Contribution of potential prognostic factors to tumor-specific survival in breast cancer patients who received Tamoxifen monotherapy (multivariate COX regression mode). (PDF 41 kb)

Supplementary Table 3

Primers and probes used. (PDF 31 kb)

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Holst, F., Stahl, P., Ruiz, C. et al. Estrogen receptor alpha (ESR1) gene amplification is frequent in breast cancer. Nat Genet 39, 655–660 (2007). https://doi.org/10.1038/ng2006

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