Reduced ING1 levels in breast cancer promotes metastasis
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Satbir Thakur1,*, Arvind K. Singla1,*, Jie Chen1, Uyen Tran1, Yang Yang1, Carolina Salazar1, Anthony Magliocco3, Alexander Klimowicz4,5, Frank R. Jirik1 and Karl Riabowol1,2
1 Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, Alberta, CANADA
2 Department of Oncology, University of Calgary, Calgary, Alberta, CANADA
3 Moffitt Cancer Center, Tampa, Florida USA
4 Functional Tissue Imaging Unit, Translational Research Laboratory, Tom Baker Cancer Center, Calgary, Alberta, CANADA
5 Present Address: Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, USA
* These authors contributed equally to this work
Karl Riabowol, email:
Keywords: ING1, epigenetics, breast cancer, metastasis, survival
Received: April 6, 2014 Accepted: May 17, 2014 Published: May 19, 2014
INhibitor of Growth 1 (ING1) expression is repressed in breast carcinomas, but its role in breast cancer development and metastasis is unknown. ING1 levels were quantified in >500 patient samples using automated quantitative fluorescence immunohistochemistry, and data were analysed for correlations to patient outcome. Effects of altering ING levels were examined in microarrays and metastasis assays in vitro, and in a mouse metastasis model in vivo. ING1 levels were lower in tumors compared to adjacent normal breast tissue and correlated with tumor size (p=0.019) and distant recurrence (p=0.001) in ER- or Her2+ patients. In these patients ING1 predicted disease-specific and distant metastasis-free survival. Transcriptome analysis showed that the pathway most affected by ING1 was breast cancer (p = 0.0008). Decreasing levels of ING1 increased, and increasing levels decreased, migration and invasion of MDA-MB231 cells in vitro. ING1 overexpression also blocked cancer cell metastasis in vivo and eliminated tumor-induced mortality in mouse models. Our data show that ING1 protein levels are downregulated in breast cancer and for the first time, we show that altering their levels regulates metastasis in vitro and in vivo, which indicates that ING1 may have a therapeutic role for inhibiting metastasis of breast cancer.
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