DNA Repair Cancer Research Articles

Polymorphisms in base excision repair genes: Breast cancer risk and individual radiosensitivity.

Breast cancer (BC) is the most common cancer among women worldwide. The aetiology and carcinogenesis of BC are not clearly defined, although genetic, hormonal, lifestyle and environmental risk factors have been established. The most common treatment for BC includes breast-conserving surgery followed by a standard radiotherapy (RT) regimen. However, radiation hypersensitivity and the occurrence of RT-induced toxicity in normal tissue may affect patients' treatment. The role of DNA repair in cancer has been extensively investigated, and an impaired DNA damage response may increase the risk of BC and individual radiosensitivity. Single nucleotide polymorphisms (SNPs) in DNA repair genes may alter protein function and modulate DNA repair efficiency, influencing the development of various cancers, including BC. SNPs in DNA repair genes have also been studied as potential predictive factors for the risk of RT-induced side effects. Here, we review the literature on the association between SNPs in base excision repair (BER) genes and BC risk. We focused on X-ray repair cross complementing group 1 (XRCC1), which plays a key role in BER, and on 8-oxoguanine DNA glycosylase 1, apurinic/apyrimidinic endonuclease 1 and poly (ADP-ribose) polymerase-1, which encode three important BER enzymes that interact with XRCC1. Although no association between SNPs and radiation toxicity has been validated thus far, we also report published studies on XRCC1 SNPs and variants in other BER genes and RT-induced side effects in BC patients, emphasising that large well-designed studies are needed to determine the genetic components of individual radiosensitivity.

Abstract 1990: Effects of pomegranate extract on proliferation, apoptosis and mRNA expression in human breast cancer cells

Abstract Pomegranates (Punica granatum L.) contain a mixture of phytochemicals such as ellagitannins, ellagic acid and anthocyanins and possess antioxidant and anticancer activities. Pomegranate juice, aqueous pomegranate extract or seed oil reduces growth of different cancer cell lines and human prostate and lung cancer xenografts. Although several potential mechanisms such as stimulation of apoptosis, inhibition of inflammation and angiogenesis have been identified, further mechanistic investigations, especially in breast cancer, are needed. In this study, we examined the growth inhibitory effects of PE in association with antioxidant activity and global gene expression changes in MCF-7 breast cancer cells. PE caused a time and concentration-dependent inhibition of cell proliferation associated with the G2/M cell cycle arrest. In addition, PE induced apoptosis in a concentration-dependent manner. High antioxidant activity of PE was confirmed using the Trolox Equivalent Antioxidant Capacity assay (Trolox assay). Our data shows that 50 µg/ml of PE, which inhibits 50% of cell growth, is equivalent to 75 µg/ml of Trolox, a water-soluble vitamin E analog, and 40 µg/ml of N-acetyl Cysteine, a well-known low molecular weight thiol antioxidant. To understand whether the antioxidant activity of PE contributed to the observed cell growth inhibition, we determined whether PE (dose range 0-50 µg/ml) and equivalent doses of N-acetyl Cysteine and Trolox inhibit MCF-7 cell growth. Only PE but not equivalent doses N-acetyl Cysteine and Trolox inhibited cell growth suggesting that the growth inhibition of PE cannot solely be attributed to its antioxidant potential. To get insight into the molecular mechanisms of action of PE we conducted gene expression profiling on the cells treated with 50% growth inhibitory dose of PE using Affymetrix Human Gene 1.0 ST Array. Our data showed that 903 gene entities were altered by PE treatment (1.5-fold cut-off, p<0.05), from which 398 were downregulated, while 505 were upregulated. Most of the genes that were downregulated by PE treatment affect processes associated with mitosis, chromosomal organization and segregation, DNA replication, DNA recombination and repair, whereas most upregulated genes constitute genes involved in the regulation of apoptosis and cell cycle. Of particular interest, PE downregulated important DNA damage response and repair genes including genes of MRE11-RAD50-NBS1 complex and BRCA1-associated genome surveillance complex. Given that targeting of DNA repair in cancer may sensitize cancer cells to drugs, these findings may have a translational potential. We are currently validating the genes at their mRNA and protein levels to identify novel ‘pomegranate-target gene’ interactions that are relevant to breast cancer. It may provide novel molecular and cellular targets for pomegranate-based anticancer approaches. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1990. doi:1538-7445.AM2012-1990

Rod specific phosphodiesterase 6 regulates human melanoma cell cytoskeleton

Precision medicine is an emerging treatment paradigm that aims to find the right therapy at the right time based on an individual's unique genetic background, environment, and lifestyle. One area of precision medicine that has had success is targeting DNA repair in cancer. DNA is exposed to constant stress and there are repair mechanisms in place to maintain genetic integrity. These repair mechanisms can be targeted as a treatment strategy. In this chapter, we will focus on current efforts to target DNA repair pathways as part of precision oncology-based treatments.

Therapeutic potential of drugs to modulate DNA repair in cancer

Most established cancer therapy regimes involve DNA-damaging chemotherapy or radiotherapy. The DNA repair capacity of the tumour, therefore, represents a mechanism of therapeutic resistance. Drugs to inhibit DNA repair pathways have been developed and they demonstrate good chemosensitisation and radiosensitisation activity in preclinical models. Two classes of DNA repair inhibitors have entered clinical trial and show promising activity. Genetic instability in tumours may be at least partially due to defects in DNA repair pathways; such defects may underlie the inherent sensitivity of some tumours to certain classes of anticancer agent. DNA repair defects may also make the tumour dependent on complimentary or back-up pathways; laboratory evidence shows that targeting these complimentary pathways results in tumour-selective therapy.

Recombinational DNA Repair in Cancer and Normal Cells: The Challenge of Functional Analysis.

A major goal of current cancer research is to understand the functional consequences of mutations in recombinational DNA repair genes. The introduction of artificial recombination substrates into living cells has evolved into a powerful tool to perform functional analysis of DNA double strand break (DSB) repair. Here, we review the principles and practice of current plasmid assays with regard to the two major DSB repair pathways, homologous recombination and nonhomologous end-joining. A spectrum of assay types is available to assess repair in a wide variety of cell lines. However, several technical challenges still need to be overcome. Understanding the alterations of DSB repair in cancers will ultimately provide a rational basis for drug design that may selectively sensitize tumor cells to ionizing radiation and chemotherapy, thereby achieving therapeutic gain.

Involvement of DNA repair in cancer and aging.

The theory of aging which proposes that DNA repair capacity declines with age and/or DNA damage accumulates with age, resulting in increasingly aberrant gene expression, is attractive but still unproven. Most results that do not support the theory are at least neutral. We propose that much of the ambiguity produced by work so far is due to (a) the difficulty of controlling all relevant variables, including particularly the proliferation state of the cells used and the location and nature of the damage being repaired, and (b) the existence of multiple and overlapping DNA repair pathways. A better knowledge of the critical, rate-limiting events in DNA repair in vivo, and the application of more sophisticated approaches for studying these events, may ultimately resolve the ambiguities. The causal relationship between DNA damage and cancer seems more secure. Declining DNA repair capacity with age would be expected to accelerate the increased incidence of cancer with age, but it is not known how important this is compared to other genetic and environmental variables. Results with genetic diseases generally support this view. Diseases characterized by DNA repair deficiencies are accompanied by phenomena that are also characteristic of normal aging, but a causal relationship has not been established. However, some of these diseases do constitute a strong risk factor for cancer. Even less convincing is a causal link between DNA repair deficiencies and aging in the so-called premature aging syndromes.