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Int J Oncol. 2016 Sep;49(3):1203-10. doi: 10.3892/ijo.2016.3588. Epub 2016 Jun 30.

Genistein targets the cancerous inhibitor of PP2A to induce growth inhibition and apoptosis in breast cancer cells.

Author information

1
Basic Medical College of Zhengzhou University, Zhengzhou, Henan 450001, P.R. China.
2
Julius L. Chambers Biomedical/Biotechnology Research Institute and Department of Biology, North Carolina Central University, Kannapolis, NC 28081, USA.

Abstract

Genistein is a soy isoflavone with phytoestrogen and tyrosine kinase inhibitory properties. High intake of soy/genistein has been associated with reduced breast cancer risk. Despite the advances in genistein-mediated antitumor studies, the underlying mechanisms remain unclear. In the present study, we investigated genistein-induced regulation of the cancerous inhibitor of protein phosphatase 2A (CIP2A), a novel oncogene frequently overexpressed in breast cancer, and its functional impact on genistein-induced growth inhibition and apoptosis. We demonstrated that genistein induced downregulation of CIP2A in MCF-7-C3 and T47D breast cancer cells, which was correlated with its growth inhibition and apoptotic activities. Overexpression of CIP2A attenuated, whereas CIP2A knockdown sensitized, genistein-induced growth inhibition and apoptosis. We further showed that genistein-induced downregulation of CIP2A involved both transcriptional suppression and proteasomal degradation. In particular, genistein at higher concentrations induced concurrent downregulation of E2F1 and CIP2A. Overexpression of E2F1 attenuated genistein-induced downregulation of CIP2A mRNA, indicating the role of E2F1 in genistein-induced transcriptional suppression of CIP2A. Taken together, our results identified CIP2A as a functional target of genistein and demonstrated that modulation of E2F1-mediated transcriptional regulation of CIP2A contributes to its downregulation. These data advance our understanding of genistein-induced growth inhibition and apoptosis, and support further investigation on CIP2A as a therapeutic target of relevant anticancer agents.

PMID:
27574003
PMCID:
PMC4948957
DOI:
10.3892/ijo.2016.3588
[Indexed for MEDLINE]
Free PMC Article

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