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The early-stage triple-negative breast cancer landscape derives a novel prognostic signature and therapeutic target

  • Preclinical study
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Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

Purpose

Triple-negative breast cancer (TNBC) is a highly heterogeneous disease. Patients with early-stage TNBCs have distinct likelihood of distant recurrence. This study aimed to develop a prognostic signature of early-stage TNBC patients to improve risk stratification.

Methods

Using RNA-sequencing data, we analyzed 189 pathologically confirmed pT1-2N0M0 TNBC patients and identified 21 mRNAs that were highly expressed in tumor and related to relapse-free survival. All-subset regression program was used for constructing a 7-mRNA signature in the training set (n = 159); the accuracy and prognostic value were then validated using an independent validation set (n = 158).

Results

Here, we profiled the transcriptome data from 189 early-stage TNBC patients along with 50 paired normal tissues. Early-stage TNBCs mainly consisted of basal-like immune-suppressed subtype and had higher homologous recombination deficiency scores. We developed a prognostic signature including seven mRNAs (ACAN, KRT5, TMEM101, LCA5, RPP40, LAGE3, CDKL2). In both the training (n = 159) and validation set (n = 158), this signature could identify patients with relatively high recurrence risks and served as an independent prognostic factor. Time-dependent receiver operating curve showed that the signature had better prognostic value than traditional clinicopathological features in both sets. Functionally, we showed that TMEM101 promoted cell proliferation and migration in vitro, which represented a potential therapeutic target.

Conclusions

Our 7-mRNA signature could accurately predict recurrence risks of early-stage TNBCs. This model may facilitate personalized therapy decision-making for early-stage TNBCs individuals.

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Data availability

The datasets analyzed during the current study are available in the Gene Expression Omnibus (GSE76250, HTA2.0) and Sequence Read Archive (SRP157974, RNA-seq).

Abbreviations

AIC:

Akaike information criterion

AUC:

Area under curve

BLIS:

Basal-like and immune-suppressed

ER:

Estrogen receptor

HER2:

Human epidermal growth factor receptor 2

HR:

Hormone receptor

HRD:

Homologous recombination deficiency

IM:

Immunomodulatory

LAR:

Luminal androgen receptor

LASSO:

Least absolute shrinkage and selection operator

MES:

Mesenchymal-like

RFS:

Relapse-free survival

ROC:

Receiver operating characteristic

PR:

Progestogen receptor

RT-qPCR:

Real-time quantitative-polymerase chain reaction

siRNA:

Small interfering RNAs

TNBC:

Triple-negative breast cancer

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Acknowledgements

This work was supported by the Program of Shanghai Academic/Technology Research Leader (20XD1421100), the Fok Ying-Tong Education Foundation for College Young Teachers (171034), the Shanghai Sailing Program (19YF1409000), the Innovation Team of Ministry of Education (IRT1223), and the Shanghai Key Laboratory of Breast Cancer (12DZ2260100). The funders had no role in the study design, data collection and analysis, or manuscript preparation.

Author information

Author notes

  1. Yun-Song Yang, Yi-Xing Ren and Cheng-Lin Liu have contributed equally to this work.

Authors and Affiliations

  1. Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, 270 Dong-An Road, Shanghai, 200032, People’s Republic of China

    Yun-Song Yang, Yi-Xing Ren, Cheng-Lin Liu, Shuang Hao, Xiao-En Xu, Xi Jin, Yi-Zhou Jiang & Zhi-Ming Shao

  2. Department of Oncology, Shanghai Medical College, Fudan University, 270 Dong-An Road, Shanghai, 200032, People’s Republic of China

    Yun-Song Yang, Yi-Xing Ren, Cheng-Lin Liu, Shuang Hao, Xiao-En Xu, Xi Jin, Yi-Zhou Jiang & Zhi-Ming Shao

  3. Institutes of Biomedical Sciences, Fudan University, 131 Dong-An Road, Shanghai, 200032, People’s Republic of China

    Zhi-Ming Shao

  4. Human Phenome Institute, Fudan University, 825 Zhangheng Road, Shanghai, 201203, People’s Republic of China

    Yun-Song Yang

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Contributions

Conception and design: Y-SY, Y-XR, C-LL, XJ, X-EX, Y-ZJ, and Z-MS; Development of methodology: Y-SY, Y-XR, X-EX, and Y-ZJ; Acquisition of data: Y-SY, Y-XR, SH, and Y-ZJ; Analysis and interpretation of data: Y-SY, Y-XR, C-LL, XJ, and Y-ZJ; Writing, review, and/or revision of the manuscript: Y-SY, Y-XR, C-LL, SH, XJ, Y-ZJ, and Z-MS; Administrative, technical, or material support: Y-SY, Y-XR, SH, XJ, X-EX, and Y-ZJ; Study supervision: Y-ZJ, Z-MS.

Corresponding authors

Correspondence to Xi Jin, Yi-Zhou Jiang or Zhi-Ming Shao.

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The independent ethics committee/institutional review board of FUSCC (Shanghai Cancer Center Ethics Committee) approved our study.

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Written informed consent from patients in our study was obtained before enrollment.

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Yang, YS., Ren, YX., Liu, CL. et al. The early-stage triple-negative breast cancer landscape derives a novel prognostic signature and therapeutic target. Breast Cancer Res Treat 193, 319–330 (2022). https://doi.org/10.1007/s10549-022-06537-z

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  • DOI: https://doi.org/10.1007/s10549-022-06537-z

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