Poster Presentation 25th Lorne Cancer Conference 2013

An Exploration of the 11q13 Breast Cancer Susceptibility Locus Using 3C and 4C Chromatin Conformation Capture Technologies (#119)

Joshua Betts 1 , Juliet French 1 , Darren Korbie 1 , Melissa Brown 1 , Stacey Edwards 1
  1. University of Queensland, St Lucia, Qld, Australia

A recent genome-wide association study conducted by Turnbull et al. in 2010 found a susceptibility locus for breast cancer in the 11q13 gene desert (1). Fine mapping of this locus revealed 5 potentially causative single nucleotide polymorphisms (SNPs) that were located in two regions possessing the characteristic epigenetic and transcription factor binding profiles of genomic regulatory elements. Our previous study (2) revealed interactions between these regulatory elements and the nearby Cyclin D1 gene (CCND1), one of the most commonly amplified gene in breast tumours and a known oncogene. One element (PRE1) proved to act as an enhancer of transcription and the other (PRE2) as a silencer. The ENCODE study found that such distal regulatory elements interacted with an average of 2.15 transcription start sites, with some interacting with greater than 10 (3). We therefore used 4C-seq to explore interactions between these elements and other genes in the 11q13 locus in an unbiased fashion.

This revealed interactions with a number of genes, in particular the MYEOV (myeloma over-expressed) gene and ORAOV1 (oral cancer over-expressed 1). We then used 3C to confirm oestrogen-responsive interactions between one of the SNP affected regulatory elements (PRE1) and these genes. A robust interaction was found between PRE1 and the ORAOV1 promoter following oestrogen stimulation of MCF7 cells. Knockdown of ORAOV1 has been previously shown to suppress CCND1 expression in a HeLa cell model (4), suggesting a possible mechanism for breast cancer pathogenesis where alterations in ORAOV1 expression affect CCND1 expression, thus secondarily affecting the proliferation of mammary epithelium.