Research Papers:

Methylation of a newly identified region of the INS-IGF2 gene determines IGF2 expression in breast cancer tumors and in breast cancer cells

Vinodh Kumar Radhakrishnan, Kameswaran Ravichandran, Chibuzo Eke, Amanda Ortiz-Vicil, Qianwei Tan, Marino De León and Daisy D. De León _

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Oncotarget. 2020; 11:3904-3920. https://doi.org/10.18632/oncotarget.27655

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Vinodh Kumar Radhakrishnan1, Kameswaran Ravichandran2, Chibuzo Eke1, Amanda Ortiz-Vicil1, Qianwei Tan1, Marino De León1 and Daisy D. De León1

1 Center for Health Disparities and Molecular Medicine, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA

2 Division of Renal Diseases and Hypertension, University of Colorado at Denver, Aurora, CO 80045, USA

Correspondence to:

Daisy D. De León,email: [email protected]

Keywords: IGF2; INS-IGF2; hypermethylation; DMR; epigenetics

Received: December 13, 2018     Accepted: June 01, 2020     Published: November 03, 2020

Copyright: © 2020 Radhakrishnan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


IGF2 is essential in breast differentiation, lactation, tumor growth, and in breast cancer (BC) development and progression. This growth factor also inhibits apoptosis and promotes metastasis and chemoresistance, contributing to more aggressive tumors. We previously demonstrated that IGF2 protein levels are higher in BC tissues from African American women than in Caucasian women. We also showed that high IGF2 protein levels are expressed in normal breast tissues of African American women while little or no IGF2 was detected in tissues from Caucasian women. Others showed that decreased DNA methylation of the IGF2 gene leads to different BC clinical features. Thus, we designed this study to determine if differentially methylated regions of the IGF2 gene correspond to IGF2 protein expression in paired (Normal/Tumor) breast tissues and in BC cell lines. Methylation analysis was performed using Sodium Bisulphite Analysis and Methylation Sensitive Restriction Enzyme digestion methods. Our results show that a unique site in the INS-IGF2 region is hypermethylated in normal breast and hypomethylated in breast cancer. We designated this region the DVDMR. Furthermore, the methylation levels in the DVDMR significantly correlated with IGF2 protein levels. This novel DMR consists of 257bp localized in the INS-IGF2 gene. We propose that methylation of DVDMR represents a novel epigenetic biomarker that determines the levels of IGF2 protein expression in breast cancer. Since IGF2 promotes metastasis and chemoresistance, we propose that IGF2 levels contribute to BC aggressiveness. Validation of IGF2 as a biomarker will improve diagnosis and treatment of BC patients.

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