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Chromosome 1q21.3 amplification is a trackable biomarker and actionable target for breast cancer recurrence

Nature Medicine volume 23, pages 1319–1330 (2017)Cite this article

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Abstract

Tumor recurrence remains the main reason for breast cancer–associated mortality, and there are unmet clinical demands for the discovery of new biomarkers and development of treatment solutions to benefit patients with breast cancer at high risk of recurrence. Here we report the identification of chromosomal copy-number amplification at 1q21.3 that is enriched in subpopulations of breast cancer cells bearing characteristics of tumor-initiating cells (TICs) and that strongly associates with breast cancer recurrence. Amplification is present in ∼10–30% of primary tumors but in more than 70% of recurrent tumors, regardless of breast cancer subtype. Detection of amplification in cell-free DNA (cfDNA) from blood is strongly associated with early relapse in patients with breast cancer and could also be used to track the emergence of tumor resistance to chemotherapy. We further show that 1q21.3-encoded S100 calcium-binding protein (S100A) family members, mainly S100A7, S100A8, and S100A9 (S100A7/8/9), and IL-1 receptor–associated kinase 1 (IRAK1) establish a reciprocal feedback loop driving tumorsphere growth. Notably, this functional circuitry can be disrupted by the small-molecule kinase inhibitor pacritinib, leading to preferential impairment of the growth of 1q21.3-amplified breast tumors. Our study uncovers the 1q21.3-directed S100A7/8/9–IRAK1 feedback loop as a crucial component of breast cancer recurrence, serving as both a trackable biomarker and an actionable therapeutic target for breast cancer.

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Figure 1: Genomic interrogation of TICs identifies 1q21.3 amplification in breast cancer.
Figure 2: 1q21.3 amplification is enriched in TICs and is associated with tumor recurrence.
Figure 3: cfDNA detection of 1q21.3 amplification is associated with recurrence and poor patient outcome.
Figure 4: 1q21.3-encoded S100A7/8/9 forms a functional feedback loop with IRAK1 to drive tumorsphere growth.
Figure 5: Pacritinib effectively disrupts the S100A7/8/9–IRAK1 feedback loop to inhibit tumorsphere growth.
Figure 6: Amplification status of 1q21.3 correlates with the efficacy of pacritinib in vitro and in vivo.

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Acknowledgements

This work was supported by the Agency for Science, Technology and Research of Singapore (A*STAR), the Margie Petersen Breast Cancer Program, and the Association of Breast Cancer (D.S.B.H.), Singapore Ministry of Health's National Medical Research Council (NMRC) Clinician Scientist Individual Research Grants (NMRC/CIRG/1464/2016 and NMRC/CG/017/2013 to E.Y.T.; NMRC/CSA/015/2009 and NMRC/CSA-SI/0004/2015 to S.C.L.), and the Danish Cancer Society (R99-A6362 and R146-A9164 to H.J.D.). This work was also supported by an A*STAR Graduate Academy (A*GA) SINGA (Singapore International Graduate Award) scholarship to G.O. We thank the Histopathology Department from the Institute of Molecular and Cell Biology, A*STAR, for their service in IHC staining and analysis.

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Author notes

  1. Jian Yuan Goh, Min Feng and Wenyu Wang: These authors contributed equally to this work.

Authors and Affiliations

  1. Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore

    Jian Yuan Goh, Min Feng, Wenyu Wang, Gokce Oguz, Siti Maryam J M Yatim, Puay Leng Lee, Yi Bao, Wai Leong Tam, Suman Sarma, Alexander Lezhava & Qiang Yu

  2. Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore

    Gokce Oguz & Qiang Yu

  3. Department of Pathology, Cytogenetics Laboratory, Singapore General Hospital, Singapore

    Tse Hui Lim & Alvin S T Lim

  4. Cancer Research Institute and School of Pharmacy, Jinan University, Guangzhou, China

    Panpan Wang & Qiang Yu

  5. Cancer Science Institute of Singapore, National University of Singapore, Singapore

    Wai Leong Tam & Soo Chin Lee

  6. Department of Oncology, Odense University Hospital, Odense, Denmark

    Annette R Kodahl & Henrik J Ditzel

  7. Department of Cancer and Inflammation Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark

    Maria B Lyng & Henrik J Ditzel

  8. Department of Translational Molecular Medicine, John Wayne Cancer Institute, Santa Monica, California, USA

    Selena Y Lin & Dave S B Hoon

  9. Division of Medical Oncology, National Cancer Centre Singapore, Singapore

    Yoon Sim Yap

  10. Department of Haematology–Oncology, National University Cancer Institute, National University Health System, Singapore

    Soo Chin Lee

  11. Department of General Surgery, Tan Tock Seng Hospital, Singapore

    Ern Yu Tan

  12. Institute of Molecular and Cellular Biology, A*STAR, Biopolis, Singapore

    Ern Yu Tan

  13. Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore

    Qiang Yu

Authors
  1. Jian Yuan Goh
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Contributions

Q.Y. supervised the project and contributed to the design and interpretation of all experiments. J.Y.G. contributed to the design, conduct, and interpretation of all experiments. M.F. performed tumor sample preparation, genomic DNA and cfDNA extraction, RNA-seq, gene knockdown, and tumorsphere assays. Y.B. performed overexpression and tumorsphere assays. W.W. and P.L.L. performed western blot analyses. G.O. performed bioinformatics and statistical analyses. W.W., M.F., and S.M.J.M.Y. performed in vivo experiments. T.H.L. and A.S.T.L. performed DNA FISH analysis. P.W., A.R.K., M.B.L., and S.Y.L. contributed to collection of patient blood samples and clinical information. A.L. and S.S. contributed digital PCR analyses. W.L.T., Y.S.Y., D.S.B.H., H.J.D., S.C.L., and E.Y.T. provided crucial reagents and patient samples and contributed to clinical data analyses and interpretation. J.Y.G. and Q.Y. wrote the manuscript with input from all co-authors.

Corresponding authors

Correspondence to Henrik J Ditzel, Soo Chin Lee, Ern Yu Tan or Qiang Yu.

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The authors declare no competing financial interests.

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Goh, J., Feng, M., Wang, W. et al. Chromosome 1q21.3 amplification is a trackable biomarker and actionable target for breast cancer recurrence. Nat Med 23, 1319–1330 (2017). https://doi.org/10.1038/nm.4405

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