Mini-review Epigenetic inactivation of DNA repair in breast cancer Somaira Nowsheen a , Khaled Aziz b , Phuoc T. Tran b , Vassilis G. Gorgoulis c , Eddy S. Yang a , Alexandros G. Georgakilas d,⇑ a Department of Radiation Oncology, Hazelrig-Salter Radiation Oncology Center, University of Alabama at Birmingham Comprehensive Cancer Center, Birmingham, AL 35294, USA b Department of Radiation Oncology & Molecular Radiation Sciences, Johns Hopkins School of Medicine, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD 21231, USA c Molecular Carcinogenesis Group, Department of Histology and Embryology, School of Medicine, University of Athens, Athens, Greece d Department of Biology, Thomas Harriot College of Arts and Sciences, East Carolina University, Greenville, NC 27858, USA article info Article history: Available online xxxx Keywords: Epigenetics Biomarkers Cancer DNA damage Breast cancer Personalized treatment Carcinogenesis abstract The study of epigenetic mechanisms in cancer, such as DNA methylation and histone modifications, has revealed a plethora of events that contribute to cancer through stable changes in the expression of genes critical to transformation pathways. In this mini review we look at the different epigenetic modifications prevalent in this neoplastic phenotype, focusing on breast cancer. Most encouragingly, research in epige- netics has led to improved survival of patients with certain forms of lymphoma and leukemia through the use of drugs that alter DNA methylation and histone acetylation. Thus, we look at the clinical utility of targeting epigenetic pathways. In addition, we explore numerous other clinical applications of epigenet- ics, in areas such as cancer screening and early detection, prevention, classification for epidemiology and prognostic purposes, and predicting outcomes after standard therapy. Ó 2012 Elsevier Ireland Ltd. All rights reserved. 1. Introduction The human genome controls cell fate in a very systematic, pre- cise way. Genomic DNA is under constant assault which often re- sults in alterations potentially transforming a normal cell to a precancerous lesion. Accumulation of these changes or mutations over time eventually leads to cancer with uncontrolled cell growth. Both genotoxic and non-genotoxic mechanisms have been impli- cated in malignant transformation. Genotoxic mechanisms involve changes in genomic DNA se- quences leading to mutations while non-genotoxic mechanisms modulate gene expression directly [1]. Mutations can either be ac- quired or inherited and are caused by both endogenous and exog- enous agents. On the other hand, epigenetics are heritable changes in phenotype or gene expression caused by mechanisms other than changes in DNA sequence. Both of these changes result in a differ- ential expression and/or function of genes, such as the changes seen when cells differentiate or become malignant. Dysregulated cell growth and apoptosis in cancer are due to genetic and epige- netic changes such as point mutations, deletions, duplications, insertions, translocations, chromosome aberrations, viral infec- tions (e.g. human papilloma virus, Epstein–Barr virus, and Hepati- tis virus), and epigenetic inactivation such as promoter hypermethylation and histone deacetylation. These mechanisms may affect the DNA sequence but ultimately change the function and regulation of the gene products or lead to gain/loss of function of critical genes. Several models of carcinogenesis have been proposed. One of the models put forth by Dr. Bert Vogelstein proposes a stepwise accumulation of genetic events including the loss of function of tu- mor suppressors such as p53 and the gain of function of oncogenes [2]. Loss of p53 function is observed in the majority of cancers and results in genomic instability, metabolic changes, insensitivity to apoptotic signals, invasiveness and motility [3,4]. Initially, an inac- tivating mutation in tumor suppressor gene leads to hyper-prolif- eration of epithelial cells and/or inactivation of DNA repair genes. The same mutation may inactivate several more tumor suppressor genes before resulting in cancer. An alternate theory accounting for both hereditary and non- hereditary cancer is Dr. Alfred Knudson’s two-hit theory of cancer causation [5]. According to his proposal, people with a hereditary susceptibility to cancer take their first hit at conception and inherit a damaged gene on one of the two chromosomes. Others inherit two normal chromosomes but receive the first hit post-conception. A subsequent damage to the same gene on the second chromo- some may lead to cancer. Therefore, people with a hereditary sus- ceptibility to cancer just need one hit during their lifetime to transform a normal cell to cancer. This model fits perfectly for can- cer such as retinoblastoma where inheritance of the first hit leads 0304-3835/$ - see front matter Ó 2012 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.canlet.2012.05.015 ⇑ Corresponding author. Address: Department of Biology, Howell Science Com- plex, East Carolina University, Greenville, NC 27858, USA. Tel.: +1 252 328 5446; fax: +1 252 328 4178. E-mail address: georgakilasa@ecu.edu (A.G. Georgakilas). Cancer Letters xxx (2012) xxx–xxx Contents lists available at SciVerse ScienceDirect Cancer Letters journal homepage: www.elsevier.com/locate/canlet Please cite this article in press as: S. Nowsheen et al., Epigenetic inactivation of DNA repair in breast cancer, Cancer Lett. (2012), http://dx.doi.org/10.1016/ j.canlet.2012.05.015