Genomic interaction profiles in breast cancer reveal altered chromatin architecture

• Published in: PloS one 2013-09, Vol.8 (9), p.e73974-e73974
• Main Authors: Zeitz, Michael J, Ay, Ferhat, Heidmann, Julia D, Lerner, Paula L, Noble, William S, Steelman, Brandon N, Hoffman, Andrew R
• Format: Article
• Language: English
• Subjects: Analysis; Biology; Breast cancer; Breast carcinoma; Breast Neoplasms - genetics; Breast Neoplasms - pathology; Cancer; Cancer genetics; Cancer research; Cell cycle; Cell Line, Tumor; Chromatin; Chromatin - genetics; Chromosome Aberrations; Chromosomes; Deoxyribonucleic acid; Development and progression; DNA; DNA Methylation; Down-Regulation; Epidermal growth factor; Epidermal growth factor receptors; Epidermal growth factors; Epigenetics; Female; Gene expression; Genes; Genetic aspects; Genome, Human; Genomes; Humans; In Situ Hybridization, Fluorescence; Insulin-Like Growth Factor Binding Protein 3 - genetics; Insulin-like growth factor-binding protein 3; Insulin-like growth factors; Medical prognosis; Medical research; Medical schools; Medicine; Metastases; Metastasis; Neoplasm Proteins - genetics; Noble, Brandon; Pathogenesis; Promoter Regions, Genetic; Prostate; Transcription; Transcription (Genetics); Transcription, Genetic; Translocation; Tumor cell lines; Tumorigenesis; Up-Regulation; Veterans
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0073974

Gene transcription can be regulated by remote enhancer regions through chromosome looping either in cis or in trans. Cancer cells are characterized by wholesale changes in long-range gene interactions, but the role that these long-range interactions play in cancer progression and metastasis is not well understood. In this study, we used IGFBP3, a gene involved in breast cancer pathogenesis, as bait in a 4C-seq experiment comparing normal breast cells (HMEC) with two breast cancer cell lines (MCF7, an ER positive cell line, and MDA-MB-231, a triple negative cell line). The IGFBP3 long-range interaction profile was substantially altered in breast cancer. Many interactions seen in normal breast cells are lost and novel interactions appear in cancer lines. We found that in HMEC, the breast carcinoma amplified sequence gene family (BCAS) 1-4 were among the top 10 most significantly enriched regions of interaction with IGFBP3. 3D-FISH analysis indicated that the translocation-prone BCAS genes, which are located on chromosomes 1, 17, and 20, are in close physical proximity with IGFBP3 and each other in normal breast cells. We also found that epidermal growth factor receptor (EGFR), a gene implicated in tumorigenesis, interacts significantly with IGFBP3 and that this interaction may play a role in their regulation. Breakpoint analysis suggests that when an IGFBP3 interacting region undergoes a translocation an additional interaction detectable by 4C is gained. Overall, our data from multiple lines of evidence suggest an important role for long-range chromosomal interactions in the pathogenesis of cancer.