Regulatory elements seen as hubs controlling multiple genes
SAN ANTONIO (Aug. 12, 2013) — Adding to the picture of what prompts breast cancers to form, researchers from the Cancer Therapy & Research Center (CTRC) at The University of Texas Health Science Center San Antonio today announced that “distant estrogen response elements” (DEREs) can act independently of oncogenes to spur tumor development.
DEREs appear to be depots or hubs that remotely and simultaneously control multiple target genes in response to estrogen stimulation, said Pei-Yin Hsu, Ph.D., lead author of the paper in Cancer Cell. As such, they are prime targets for the study of novel therapies for breast cancer and could also be useful in diagnosis.
Where DEREs are multiplied or present in abnormal numbers, this contributes to tumor development, especially in estrogen receptor-positive breast cancers, said study senior author Tim Hui-Ming Huang, Ph.D., deputy director of the CTRC. Decreasing the number of DERE copies could have therapeutic potential to treat women with this aggressive form of cancer, Dr. Huang said.
DEREs at 2 sites
The researchers analyzed two DERE clusters on human chromosomes 17 and 20. They found that the DEREs induce pro-growth factors and inhibit growth-suppressing genes. “It is worthwhile to note that DERE-DERE interactions, instead of DERE interactions with genes, may also contribute to tumor development,” Dr. Hsu said. The team found a correlation between a subset of DERE-regulated genes and tamoxifen resistance. Tamoxifen is a widely prescribed hormone therapy for breast cancer. It may be possible to evaluate how a woman will respond to tamoxifen by measuring DERE activity, Dr. Hsu said.
In addition, the two DEREs that were studied could turn out to be good biomarkers for whether a woman will develop estrogen receptor-positive breast cancer. “Perhaps we could prevent some cases of this cancer,” Dr. Huang said. Several units of the UT Health Science Center joined in the work, including the Greehey Children’s Cancer Research Institute, the Institute of Biotechnology, and the Department of Molecular Medicine and Department of Epidemiology and Biostatistics in the School of Medicine.
This work was supported by R01 CA069065, R01 ES017594, U01 ES015986 (Gene and Environment Initiative), U54 CA113001 (Integrative Cancer Biology Program), and P30 CA054174 (Cancer Center Support Grant) at the U.S. National Institutes of Health and by generous gifts from the Cancer Therapy & Research Center Foundation and the Max and Minnie Tomerlin Voelcker Fund.
Amplification of Distant Estrogen Response Elements Deregulates Target Genes Associated with Tamoxifen Resistance in Breast Cancer
Pei-Yin Hsu,1 Hang-Kai Hsu,1 Xun Lan,6 Liran Juan,9 Pearlly S. Yan,7 Jadwiga Labanowska,8 Nyla Heerema,8 Tzu-Hung Hsiao,4 Yu-Chiao Chiu,5 Yidong Chen,3,4 Yunlong Liu,9 Lang Li,9 Rong Li,1 Ian M. Thompson,2 Kenneth P. Nephew,10 Zelton D. Sharp,1 Nameer B. Kirma,1 Victor X. Jin,6 and Tim H.-M. Huang1,* Departments of 1 Molecular Medicine/Institute of Biotechnology, 2 Urology, and 3 Epidemiology and Biostatistics, 4 Greehey Children’s Cancer Research Institute, Cancer Therapy & Research Center, The University of Texas Health Science Center at San Antonio, TX 78245, USA 5 Graduate Institute of Biomedical Electronics and Bioinformatics, National Taiwan University, Taipei, Taiwan Departments of 6 Biomedical Informatics, 7 Molecular Virology, Immunology, and Medical Genetics, and 8 Pathology, The Ohio State University, Columbus, OH 43210, USA 9 Center of Computational Biology and Bioinformatics and Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA 10 Medical Sciences, Indiana University School of Medicine, Bloomington, IN 47405, USA
About the Cancer Therapy & Research Center at The University of Texas Health Science Center at San Antonio
The Cancer Therapy & Research Center (CTRC) at The University of Texas Health Science Center at San Antonio is one of the elite academic cancer centers in the country to be named a National Cancer Institute (NCI) Designated Cancer Center, and is one of only four in Texas. A leader in developing new drugs to treat cancer, the CTRC Institute for Drug Development (IDD) conducts one of the largest oncology Phase I clinical drug programs in the world, and participates in development of cancer drugs approved by the U.S. Food & Drug Administration. For more information, visit http:www.ctrc.net.