Genomic Interaction Profiles in Breast Cancer Reveal Altered Chromatin Architecture

Abstract

<div><p>Gene transcription can be regulated by remote enhancer regions through chromosome looping either in <i>cis</i> or in <i>trans</i>. 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 <i>IGFBP3</i>, 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 <i>IGFBP3</i> 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 (<i>BCAS</i>) 1–4 were among the top 10 most significantly enriched regions of interaction with <i>IGFBP3.</i> 3D-FISH analysis indicated that the translocation-prone <i>BCAS</i> genes, which are located on chromosomes 1, 17, and 20, are in close physical proximity with <i>IGFBP3</i> and each other in normal breast cells. We also found that epidermal growth factor receptor (<i>EGFR),</i> a gene implicated in tumorigenesis, interacts significantly with <i>IGFBP3</i> and that this interaction may play a role in their regulation. Breakpoint analysis suggests that when an <i>IGFBP3</i> 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.</p></div