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Identification and functional analysis of 9p24 amplified genes in human breast cancer

Abstract

Previously, our group identified a novel amplicon at chromosome 9p24 in human esophageal and breast cancers, and cloned the novel gene, GASC1 (gene amplified in squamous cell carcinoma 1, also known as JMJD2C/KDM4C), from this amplicon. GASC1 is a histone demethylase involved in the deregulation of histone methylation in cancer cells. In the current study, we aimed to comprehensively characterize the genes in the 9p24 amplicon in human breast cancer. We performed extensive genomic analyses on a panel of cancer cell lines and narrowed the shortest region of overlap to approximately 2 Mb. Based on statistical analysis of copy number increase and overexpression, the 9p24 amplicon contains six candidate oncogenes. Among these, four genes (GASC1 UHRF2, KIAA1432 and C9orf123) are overexpressed only in the context of gene amplification while two genes (ERMP1 and IL33) are overexpressed independent of the copy number increase. We then focused our studies on the UHRF2 gene, which has a potential involvement in both DNA methylation and histone modification. Knocking down UHRF2 expression inhibited the growth of breast cancer cells specifically with 9p24 amplification. Conversely, ectopic overexpression of UHRF2 in non-tumorigenic MCF10A cells promoted cell proliferation. Furthermore, we demonstrated that UHRF2 has the ability to suppress the expression of key cell-cycle inhibitors, such as p16INK4a, p21Waf1/Cip1 and p27Kip1. Taken together, our studies support the notion that the 9p24 amplicon contains multiple oncogenes that may integrate genetic and epigenetic codes and have important roles in human tumorigenesis.

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Acknowledgements

This work was supported by Grants from the Department of Defense Breast Cancer Program (BC086177 and BC083945) to Zeng-Quan Yang, a grant from the National Institutes of Health grant RO1 CA100724 to Stephen P. Ethier, and the Taubman Scholar Award from Taubman Institute to Max S. Wicha. The Biostatistics Core of the Karmanos Cancer Institute is supported by the National Institutes of Health Grant P30-CA022453-29. We thank Michele L. Dziubinski for technical assistance on the cell culture. We thank Dr Steve Guest, Dr Aliccia Bollig-Fischer and Kimberly Lyons for discussions and careful reading of a draft manuscript.

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Wu, J., Liu, S., Liu, G. et al. Identification and functional analysis of 9p24 amplified genes in human breast cancer. Oncogene 31, 333–341 (2012). https://doi.org/10.1038/onc.2011.227

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