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Breast Cancer Research and Treatment

, Volume 145, Issue 1, pp 45–59 | Cite as

Discovery of structure-based small molecular inhibitor of αB-crystallin against basal-like/triple-negative breast cancer development in vitro and in vivo

  • Zhijuan Chen
  • Qing Ruan
  • Song Han
  • Lei Xi
  • Wenguo Jiang
  • Huabei Jiang
  • David A. Ostrov
  • Jun CaiEmail author
Preclinical Study

Abstract

αB-crystallin (CRYAB) is present at a high frequency in poor prognosis basal-like breast tumours, which are largely absent of oestrogen, progesterone receptors and HER2 known as triple-negative breast cancer (TNBC). CRYAB functions as a molecular chaperone to bind to and correct intracellular misfolded/unfolded proteins such as vascular endothelial growth factor (VEGF), preventing non-specific protein aggregations under the influence of the tumour microenvironment stress and/or anti-cancer treatments including bevacizumab therapy. Directly targeting CRYAB can sensitize tumour cells to chemotherapeutic agents and decrease tumour aggressiveness. However, growing evidence shows that CRYAB is a critical adaptive response element after ischemic heart disease and stroke, implying that directly targeting CRYAB might cause serious unwanted side effects. Here, we used structure-based molecular docking of CRYAB and identified a potent small molecular inhibitor, NCI-41356, which can strongly block the interaction between CRYAB and VEGF165 without affecting CRYAB levels. The disruption of the interaction between CRYAB and VEGF165 elicits in vitro anti-tumour cell proliferation and invasive effects through the down-regulation of VEGF signalling in the breast cancer cells. The observed in vitro anti-tumour angiogenesis of endothelial cells might be attributed to the down-regulation of paracrine VEGF signalling in the breast cancer cells after treatment with NCI-41356. Intraperitoneal injection of NCI-41356 greatly inhibits the tumour growth and vasculature development in in vivo human breast cancer xenograft models. Our findings provide ‘proof-of-concept’ for the development of highly specific structure-based alternative targeted therapy for the prevention and/or treatment of TNBC.

Keywords

CRYAB VEGF165 Small molecular inhibitor TNBC 

Abbreviations

TNBC

Triple-negative breast cancer

CRYAB

αB-crystallin

VEGF

Vascular endothelial growth factor

ER

Oestrogen receptor

PG

Progesterone receptor

HER2

Human EGF (epidermal growth factor) receptor 2

Notes

Acknowledgments

This work was supported by Bankhead Coley Cancer Research Program (09BN-04) from the state Florida department of health in USA. Mr. Weilin Cai and Miss. Sioned Owen are acknowledged for assistance with proofreading.

Conflict of interest

The authors declare that they have no competing interests.

Supplementary material

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Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Zhijuan Chen
    • 1
  • Qing Ruan
    • 1
  • Song Han
    • 2
  • Lei Xi
    • 3
  • Wenguo Jiang
    • 4
  • Huabei Jiang
    • 3
  • David A. Ostrov
    • 5
  • Jun Cai
    • 1
    • 4
    Email author
  1. 1.Department of Anatomy and Cell BiologyUniversity of FloridaGainesvilleUSA
  2. 2.Department of SurgeryUniversity of FloridaGainesvilleUSA
  3. 3.Department of Biomedical EngineeringUniversity of FloridaGainesvilleUSA
  4. 4.Cardiff University-Peking University Cancer Institute, Institute of Cancer & GeneticsCardiff UniversityCardiffUK
  5. 5.Department of Pathology, Immunology and Laboratory MedicineUniversity of FloridaGainesvilleUSA

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