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ERβ modulates genistein’s cisplatin-enhancing activities in breast cancer MDA-MB-231 cells via P53-independent pathway

  • Ren Liu
  • Xiaolin Xu
  • Chenglin Liang
  • Xin Chen
  • Xiaowei Yu
  • Hongfei Zhong
  • Wenxiu Xu
  • Yu Cheng
  • Wei Wang
  • Yudong Wu
  • Lehan Yu
  • Xiaojuan HuEmail author
Article
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Abstract

As one of the typical food-derived phytoestrogens, genistein (GEN) could bind to estrogen receptor (ER) and was reported to be closely related to breast cancer. Our former research showed that GEN interfered with the anti-tumor effects of cisplatin (CIS) in breast cancer MCF-7 (ERα+/ERβ−) cells. However, it is not clear whether ER expression pattern affects GEN’s modulation on CIS’s activity. In the present study, breast cancer ERβ knockdown (ERβKD) MDA-MB-231 (ERα−/ERβ+) cell model was established via ERβ RNAi lentivirus infection. The role of ERβ expression in GEN’s bioeffects on cells’ response to CIS was investigated and was further double-checked by pathway-specific inhibitor PHTPP. Consistent results were harvested through cell viability analysis, cell cycle distribution flow cytometry, TUNEL staining, and expression detection of key biomarkers, Bax, Bcl-2, P21, P53, and cleaved caspase-3. Compared with the control group, PHTPP-treated or ERβKD cells exhibited higher sensitivity to both GEN and CIS treatment. GEN and CIS showed synergistic effects only in ERβ-deficient cells. This effect mainly resulted in G2 phase arresting and apoptosis induction with the upregulation of P21 and Bax/Bcl-2 protein level. Besides, P53 expression was strikingly suppressed in ERβ-deficient cells. This indicated ERβ pathway deficiency might enhance GEN–CIS bioactivity via the downregulation of P53. In summary, our data imply that daily intake of GEN-rich diet could collaborate with CIS anti-tumor treatment in ERα−/ERβ− breast cancer cases. ERβ pathway might be one of the potential targets which elicit GEN’s positive effects in ERα− breast cancer patients.

Keywords

Genistein Cisplatin Breast cancer ERβ Chemotherapy P53-independent 

Abbreviations

GEN

Genistein

ER

Estrogen receptor

CIS

Cisplatin

ERβKD

ERβ Knockdown

TNBC

Triple-negative breast cancer

SERMs

Selective estrogen receptor modulators

DPN

(4-Hydroxyphenyl)-propionitrile

Notes

Acknowledgements

This work was supported by the National Natural Science Foundation of China (Grant Number: 81460468); the Youth Science Funding Program of Jiangxi Province (Grant Number: 20142BAB215044) and Nanchang University Innovation Funding Project for Graduate Students (Grant Number: CX2018192).

Compliance with ethical standards

Conflict of interest

All authors declare no potential conflicts of interest.

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Ren Liu
    • 1
  • Xiaolin Xu
    • 1
  • Chenglin Liang
    • 1
  • Xin Chen
    • 1
  • Xiaowei Yu
    • 1
  • Hongfei Zhong
    • 1
  • Wenxiu Xu
    • 1
  • Yu Cheng
    • 1
  • Wei Wang
    • 1
  • Yudong Wu
    • 2
  • Lehan Yu
    • 1
  • Xiaojuan Hu
    • 1
    Email author
  1. 1.Department of Biochemistry and Molecular Biology, School of Basic Medical ScienceNanchang UniversityNanchangChina
  2. 2.Department of Breast SurgeryJiangxi Cancer HospitalNanchangChina

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