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Breast Cancer Research and Treatment

, Volume 148, Issue 2, pp 423–436 | Cite as

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

  • Ming Zheng
  • Yinghui Zhou
  • Xiangmin Yang
  • Juan Tang
  • Ding Wei
  • Yang Zhang
  • Jian-Li Jiang
  • Zhi-nan ChenEmail author
  • Ping ZhuEmail author
Epidemiology

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.

Keywords

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

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

Notes

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.

Supplementary material

10549_2014_3172_MOESM1_ESM.pdf (560 kb)
Supplementary material 1 (PDF 559 kb)

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Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Ming Zheng
    • 1
    • 2
  • Yinghui Zhou
    • 1
  • Xiangmin Yang
    • 1
  • Juan Tang
    • 1
  • Ding Wei
    • 1
  • Yang Zhang
    • 1
  • Jian-Li Jiang
    • 1
  • Zhi-nan Chen
    • 1
    Email author
  • Ping Zhu
    • 2
    Email author
  1. 1.State Key Laboratory of Cancer Biology, Cell Engineering Research Center & Department of Cell BiologyThe Fourth Military Medical UniversityXi’anPeople’s Republic of China
  2. 2.Department of Clinical Immunology, Xijing HospitalThe Fourth Military Medical UniversityXi’anPeople’s Republic of China

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