Origins of DNA Replication and Amplification in the Breast Cancer Genome
Abstract
Genetic instability and rearrangements, including gene amplification, is a hallmark of many cancers (Santarius et al. 2010). Gene amplification is common in breast cancer genomes (McBride et al. 2012). Amplification of the HER2 (ErbB2/Neu) gene, which encodes human epidermal growth factor 2, occurs in ~25% of invasive breast cancers and in 50-60% of ductal carcinoma in situ. HER2 amplification and concomitant over-expression of this growth factor promotes cancer cell growth in a variety of tissue environments, acting as a metastasis-promoting factor. There are many examples of DNA amplification of other oncogenes as well. DNA amplification plays a role in establishing the malignant cell phenotype in cancer (Nikolsky et al., 2008). It would be desirable to prevent gene amplification, thereby moderating the aggressive growth of breast cancer cells. The problem is that no one knows what triggers gene amplification. Our current research in a model system suggests that the trigger may be a transcription factor such as the receptor for the steroid hormone estrogen. Cancer is believed to occur after a build-up of somatic mutations or other genomic changes. We wish to ask if a genomic change (genetic or epigenetic) might produce novel binding site(s) for the estrogen receptor (ER) near a replication origin to cause re-replication. The novel ER binding site would be absent in normal cells prior to amplification. Our hypothesis, based on our recent data from a model system, is that the ER interacts with the replication machinery to drive re-replication, resulting in amplification.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2013
- Accession Number
- ADA599511
Entities
People
- Alexander Brodsky
- Ben Raphael
- Susan A. Gerbi
Organizations
- Brown University