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

Jian Yuan Goh, Min Feng, Wenyu Wang, Gokce Oguz, Siti Maryam J M Yatim, Puay Leng Lee, Yi Bao, Tse Hui Lim, Panpan Wang, Wai Leong Tam, Annette R Kodahl, Maria B Lyng, Suman Sarma, Selena Y Lin, Alexander Lezhava, Yoon Sim Yap, Alvin S T Lim, Dave S B Hoon, Henrik J Ditzel, Soo Chin LeeErn Yu Tan, Qiang Yu

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Resumé

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.

OriginalsprogEngelsk
TidsskriftNature Medicine
Vol/bind23
Udgave nummer11
Sider (fra-til)1319–1330
ISSN1078-8956
DOI
StatusUdgivet - 2017

Fingeraftryk

Biomarkers
Chromosomes
Amplification
Tumors
Interleukin-1 Receptor-Associated Kinases
Bearings (structural)
Feedback
Calcium-Binding Proteins
Chemotherapy
Neoplasms
Blood
Phosphotransferases
Cells
Growth
Molecules
DNA

Citer dette

Goh, J. Y., Feng, M., Wang, W., Oguz, G., Yatim, S. M. J. M., Lee, P. L., ... Yu, Q. (2017). Chromosome 1q21.3 amplification is a trackable biomarker and actionable target for breast cancer recurrence. Nature Medicine, 23(11), 1319–1330. https://doi.org/10.1038/nm.4405
Goh, Jian Yuan ; Feng, Min ; Wang, Wenyu ; Oguz, Gokce ; Yatim, Siti Maryam J M ; Lee, Puay Leng ; Bao, Yi ; Lim, Tse Hui ; Wang, Panpan ; Tam, Wai Leong ; Kodahl, Annette R ; Lyng, Maria B ; Sarma, Suman ; Lin, Selena Y ; Lezhava, Alexander ; Yap, Yoon Sim ; Lim, Alvin S T ; Hoon, Dave S B ; Ditzel, Henrik J ; Lee, Soo Chin ; Tan, Ern Yu ; Yu, Qiang. / Chromosome 1q21.3 amplification is a trackable biomarker and actionable target for breast cancer recurrence. I: Nature Medicine. 2017 ; Bind 23, Nr. 11. s. 1319–1330.
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title = "Chromosome 1q21.3 amplification is a trackable biomarker and actionable target for breast cancer recurrence",
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.",
keywords = "Journal Article",
author = "Goh, {Jian Yuan} and Min Feng and Wenyu Wang and Gokce Oguz and Yatim, {Siti Maryam J M} and Lee, {Puay Leng} and Yi Bao and Lim, {Tse Hui} and Panpan Wang and Tam, {Wai Leong} and Kodahl, {Annette R} and Lyng, {Maria B} and Suman Sarma and Lin, {Selena Y} and Alexander Lezhava and Yap, {Yoon Sim} and Lim, {Alvin S T} and Hoon, {Dave S B} and Ditzel, {Henrik J} and Lee, {Soo Chin} and Tan, {Ern Yu} and Qiang Yu",
year = "2017",
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Goh, JY, Feng, M, Wang, W, Oguz, G, Yatim, SMJM, Lee, PL, Bao, Y, Lim, TH, Wang, P, Tam, WL, Kodahl, AR, Lyng, MB, Sarma, S, Lin, SY, Lezhava, A, Yap, YS, Lim, AST, Hoon, DSB, Ditzel, HJ, Lee, SC, Tan, EY & Yu, Q 2017, 'Chromosome 1q21.3 amplification is a trackable biomarker and actionable target for breast cancer recurrence', Nature Medicine, bind 23, nr. 11, s. 1319–1330. https://doi.org/10.1038/nm.4405

Chromosome 1q21.3 amplification is a trackable biomarker and actionable target for breast cancer recurrence. / Goh, Jian Yuan; Feng, Min; Wang, Wenyu; Oguz, Gokce; Yatim, Siti Maryam J M; Lee, Puay Leng; Bao, Yi; Lim, Tse Hui; Wang, Panpan; Tam, Wai Leong; Kodahl, Annette R; Lyng, Maria B; Sarma, Suman; Lin, Selena Y; Lezhava, Alexander; Yap, Yoon Sim; Lim, Alvin S T; Hoon, Dave S B; Ditzel, Henrik J; Lee, Soo Chin; Tan, Ern Yu; Yu, Qiang.

I: Nature Medicine, Bind 23, Nr. 11, 2017, s. 1319–1330.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - Chromosome 1q21.3 amplification is a trackable biomarker and actionable target for breast cancer recurrence

AU - Goh, Jian Yuan

AU - Feng, Min

AU - Wang, Wenyu

AU - Oguz, Gokce

AU - Yatim, Siti Maryam J M

AU - Lee, Puay Leng

AU - Bao, Yi

AU - Lim, Tse Hui

AU - Wang, Panpan

AU - Tam, Wai Leong

AU - Kodahl, Annette R

AU - Lyng, Maria B

AU - Sarma, Suman

AU - Lin, Selena Y

AU - Lezhava, Alexander

AU - Yap, Yoon Sim

AU - Lim, Alvin S T

AU - Hoon, Dave S B

AU - Ditzel, Henrik J

AU - Lee, Soo Chin

AU - Tan, Ern Yu

AU - Yu, Qiang

PY - 2017

Y1 - 2017

N2 - 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.

AB - 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.

KW - Journal Article

U2 - 10.1038/nm.4405

DO - 10.1038/nm.4405

M3 - Journal article

C2 - 28967919

VL - 23

SP - 1319

EP - 1330

JO - Nature Medicine

JF - Nature Medicine

SN - 1078-8956

IS - 11

ER -