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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

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support SIMILAR CONTENT BEING VIEWED BY OTHERS EXPLORING THE PROGNOSTIC SIGNIFICANCE OF ARM-LEVEL COPY NUMBER ALTERATIONS IN TRIPLE-NEGATIVE BREAST CANCER Article Open access 14 May 2024

_PIK3CA_ CO-OCCURRING MUTATIONS AND COPY-NUMBER GAIN IN HORMONE RECEPTOR POSITIVE AND HER2 NEGATIVE BREAST CANCER Article Open access 18 February 2022 COMPLEX REARRANGEMENTS FUEL ER+ AND

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Download references 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 and Wenyu Wang: These authors contributed equally to this work. AUTHORS AND

AFFILIATIONS * 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 * Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore,

Singapore Gokce Oguz & Qiang Yu * Department of Pathology, Cytogenetics Laboratory, Singapore General Hospital, Singapore Tse Hui Lim & Alvin S T Lim * Cancer Research Institute and

School of Pharmacy, Jinan University, Guangzhou, China Panpan Wang & Qiang Yu * Cancer Science Institute of Singapore, National University of Singapore, Singapore Wai Leong Tam & Soo

Chin Lee * Department of Oncology, Odense University Hospital, Odense, Denmark Annette R Kodahl & Henrik J Ditzel * Department of Cancer and Inflammation Research, Institute of

Molecular Medicine, University of Southern Denmark, Odense, Denmark Maria B Lyng & Henrik J Ditzel * Department of Translational Molecular Medicine, John Wayne Cancer Institute, Santa

Monica, California, USA Selena Y Lin & Dave S B Hoon * Division of Medical Oncology, National Cancer Centre Singapore, Singapore Yoon Sim Yap * Department of Haematology–Oncology,

National University Cancer Institute, National University Health System, Singapore Soo Chin Lee * Department of General Surgery, Tan Tock Seng Hospital, Singapore Ern Yu Tan * Institute of

Molecular and Cellular Biology, A*STAR, Biopolis, Singapore Ern Yu Tan * Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore Qiang Yu Authors * Jian Yuan Goh View author

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author publications You can also search for this author inPubMed Google Scholar * Alvin S T Lim View author publications You can also search for this author inPubMed Google Scholar * Dave S

B Hoon View author publications You can also search for this author inPubMed Google Scholar * Henrik J Ditzel View author publications You can also search for this author inPubMed Google

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 Google Scholar * Qiang Yu View author publications You can also search for this author inPubMed Google Scholar 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. ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no competing financial interests. SUPPLEMENTARY

INFORMATION SUPPLEMENTARY TEXT AND FIGURES Supplementary Figures 1–11 and Supplementary Tables 1–15. (PDF 1596 kb) LIFE SCIENCES REPORTING SUMMARY (PDF 129 KB) SUPPLEMENTARY DATA Uncropped

Immunoblots. (PDF 754 kb) RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE 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 Download citation * Received: 26 May 2017 * Accepted:

18 August 2017 * Published: 25 September 2017 * Issue Date: 01 November 2017 * DOI: https://doi.org/10.1038/nm.4405 SHARE THIS ARTICLE Anyone you share the following link with will be able

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