Article

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

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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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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.

Author information

Author notes

    • Jian Yuan Goh
    • , Min Feng
    •  & Wenyu Wang

    These authors contributed equally to this work.

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. Cytogenetics Laboratory, Department of Pathology, 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

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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.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

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

Supplementary information

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  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–11 and Supplementary Tables 1–15.

  2. 2.

    Life Sciences Reporting Summary

  3. 3.

    Supplementary Data

    Uncropped Immunoblots.