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High GINS2 transcript level predicts poor prognosis and correlates with high histological grade and endocrine therapy resistance through mammary cancer stem cells in breast cancer patients

Breast Cancer Research and Treatment volume 148, pages 423–436 (2014)Cite this article

Abstract

GINS2, a subunit of the GINS complex, is overexpressed in lung adenocarcinoma and metastatic breast tumor; however, its prognostic power and possible molecular mechanisms in breast cancer (BC) remain unclear. In this study, we aimed to explore the function of GINS2 in BC. The association between GINS2 transcript level and the clinical outcome of BC patients were estimated using Kaplan–Meier plots, multivariate cox regression analysis, forest plots, and receiver operating characteristics curves. Gene set enrichment analysis (GSEA) was performed to explore the mechanisms underlying the effects of the GINS2 transcript. High GINS2 transcript level was correlated with poor relapse free survival (log-rank P ≤ 0.001 in six cohorts; forest plot: total n = 1,420, total RR = 1.72, 95 % CI 1.45–2.03; multivariate cox regression analysis: n = 906, HR 2.36, 95 % CI 1.88–2.97), and distant metastasis free survival (log-rank P < 0.01 in 3 cohorts; forest plot: total n = 691, total RR 1.91, 95 % CI 1.36–2.67; multivariate cox regression analysis: n = 442, HR 2.43, 95 % CI 1.70–3.47). BC patients with higher GINS2 transcript levels showed poorer tamoxifen efficacy in a dose-dependent manner. GINS2 expression was significantly downregulated under mutated p53-depleted condition in MDA-468 and MDA-MB-231 cells, upregulated in mammary cancer stem cells (MaCSCs) (P = 0.003), and correlated with upregulated genes in mammary stem cells (GSEA: P < 0.01). Our study, for the first time, demonstrates that GINS2 is an independent prognostic marker and is associated with lung metastasis, histological grade, and endocrine therapy resistance in BC patients, which may attribute to mutant p53 and MaCSCs.

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Abbreviations

BC:

Breast cancer

RFS:

Relapse free survival

DMFS:

Distant metastasis free survival

DSS:

Disease-specific survival

HR:

Hazard ratio

CI:

Confidence interval

ER:

Estrogen receptor

PgR:

Progesterone receptor

ESRRA:

Estrogen receptor 1

GEO:

Gene Expression Omnibus

GSEA:

Gene Set Enrichment Analysis

ROC:

Curve receiver operating characteristics curve

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Acknowledgments

We thank Pan Luxiang, Guo Xu, and Prof. Xing Jinliang for their technical assistance in this project. This work was supported by NO. 81030058 from the National Natural Science Foundation of China and NO. 2015CB553704 from the National Basic Research Program.

Conflict of interest

We declare no potential competing financial interests. The experiments described in the manuscript comply with the current laws of the countries in which they were performed.

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Authors and Affiliations

  1. State Key Laboratory of Cancer Biology, Cell Engineering Research Center & Department of Cell Biology, The Fourth Military Medical University, Xi’an, People’s Republic of China

    Ming Zheng, Yinghui Zhou, Xiangmin Yang, Juan Tang, Ding Wei, Yang Zhang, Jian-Li Jiang & Zhi-nan Chen

  2. Department of Clinical Immunology, Xijing Hospital, The Fourth Military Medical University, Xi’an, People’s Republic of China

    Ming Zheng & Ping Zhu

Authors
  1. Ming Zheng
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  2. Yinghui Zhou
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  4. Juan Tang
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Corresponding authors

Correspondence to Zhi-nan Chen or Ping Zhu.

Additional information

Zheng Ming and Zhou Yinghui contributed equally to this work.

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Zheng, M., Zhou, Y., Yang, X. et al. High GINS2 transcript level predicts poor prognosis and correlates with high histological grade and endocrine therapy resistance through mammary cancer stem cells in breast cancer patients. Breast Cancer Res Treat 148, 423–436 (2014). https://doi.org/10.1007/s10549-014-3172-7

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Keywords

  • Breast cancer
  • GINS2
  • Relapse
  • Metastasis
  • Endocrine therapy resistance
  • Mammary cancer stem cell