Breast cancer is the second leading cause of cancer deaths in women in the United States. Hereditary breast cancer accounts for approximately 5-10% of all breast cancer cases among women. It has been speculated that reactive oxygen species (ROS) produced by oxidative stress may play a major role in the etiology of breast cancer as well as other forms of cancer. ROS are the major source of endogenous DNA damage in aerobic organisms and the hydroxyl radical is the most reactive of these radicals. The interaction of hydroxyl radical with the genomic DNA results in a plethora of modified bases and sugars, 8,5-cyclopurine-2-deoxynucleosides, DNA-protein cross-links, abasic sites and strand breaks. Concomitant damage to the sugar and purine moieties of the same nucleoside in DNA by hydroxyl radical causes the formation of 8,5-cyclopurine-2-deoxyribonucleosides with both (5R) and (5S) diastereomers. Numerous oxidatively induced DNA lesions have been identified in mammalian cells. These lesions are mutagenic and/or lethal, and may therefore be critical in carcinogenesis. One of the oxidatively induced DNA lesion, 8-hydroxyguanine (8-OH-Gua) mispairs with adenine during DNA replication causing GC_TA transversion mutations. Another oxidatively induced DNA lesion, 8-hydroxyadenine (8-OH-Ade) is also mutagenic in cells and mispairs with guanine causing A_C transversion mutations. Furthermore, 2,6-diamino-4-hydroxy-5-formamidopyrimidine (FapyGua) and 4,6-diamino-5-formamidopyrimidine (FapyAde) have been identified as mutagenic lesions as well. On the other hand, (5S)-8,5-cyclo-2-deoxyadenosine (S-cdA) blocks mammalian polymerase and reduces gene expression. ? In order to maintain proper genetic integrity and to minimize cancer risk, organisms have evolved elaborate mechanisms for repairing DNA damage. Oxidatively induced DNA base lesions such as 8-OH-Gua, 8-OH-Ade, FapyGua and FapyAde are repaired by the base excision repair (BER) pathway. Studies have shown that S-cdA is repaired by nucleotide excision repair rather than BER due to the presence of the covalent bond linking C8 of the base to C-5 of the sugar moiety in the same nucleoside BER differs from NER in that it removes the damaged base by the action of a specific DNA glycosylase/lyase, whereas, in NER, a multiprotein complex removes the damaged base as part of a larger fragment comprising multiple nucleotides. ? Several lines of evidence have implicated oxidatively induced DNA damage in breast cancer. Furthermore, oxidatively induced DNA lesions such as 8-OH-Gua, 8-OH-Ade and 5-(hydroxymethyl)-uracil have been found to accumulate in cancerous breast tissues and in blood of breast cancer patients. Interestingly, breast stromal DNA of some women between the ages of 33 and 46 accumulate elevated levels of several oxidatively induced DNA lesions consistent with the known sharp increase in breast cancer incidence within this age group.Other studies include studies by Malins et al., showing increased hydroxyl radical-induced DNA damage in DNA of invasive ductal breast carcinoma tissues relative to normal breast tissue. Olinski et al., showed that free radical-induced DNA damage is elevated in chromatin of various surgically removed malignant tissues from the colon, stomach, ovary, brain and lung relative to the surrounding non-malignant tissues. In addition, peripheral blood lymphocytes of women at high risk of developing breast cancer have been shown to be deficient in the repair of X-irradiation-induced DNA damage. Furthermore our laboratory recently showed that mitochondrial extracts but not nuclear extracts of breast cancer cell lines, MCF-7 and MDA-MB-468 are defective in the repair of 8-OH-Gua, consistent with increased levels of ROS in the mitochondria produced during the electron transport. It has also been shown that cell free extracts of HCC1937 cell line are defective in transcription-coupled repair (TCR) of 8-OH-Gua. Here, we show that HCC1937 breast cancer cells are deficient in the repair of 8-OH-Gua when compared to nonmalignant mammary epithelial cells. We further have shown that HCC1937 breast cancer cells express undetectable levels of hOGG1. In addition, these cells accumulate elevated levels of 8-OH-Gua after H2O2 challenge despite a cellular repair period at 37oC. The repair of 8-OH-Gua was stimulated by addition of purified hOGG1 in vitro and in vivo by transient expression of hOGG1 in HCC1937 cells. This study directly implicates hOGG1 in the defective repair of 8-OH-Gua in HCC1937 breast cancer cells. All these findings point to DNA repair deficiency as a risk factor for breast cancer development and support the hypothesis that oxidatively induced DNA damage may play a causative role in breast carcinogenesis. In our most recent work, we analyzed the levels of four oxidatively induced DNA lesions in the breast cancer cell lines, MCF-7 and HCC1937 relative to the non-malignant cell lines, AG11134 and HCC1937BL before and after exposure to H2O2 followed by a repair incubation period. The levels of these lesions were compared to the levels in the untreated samples.
|Nyaga, Simon G; Lohani, Althaf; Evans, Michele K (2008) Deficient repair of 8-hydroxyguanine in the BxPC-3 pancreatic cancer cell line. Biochem Biophys Res Commun 376:336-40|
|Rodriguez, Henry; Jaruga, Pawel; Leber, Dennis et al. (2007) Lymphoblasts of women with BRCA1 mutations are deficient in cellular repair of 8,5'-Cyclopurine-2'-deoxynucleosides and 8-hydroxy-2'-deoxyguanosine. Biochemistry 46:2488-96|
|Evans, M K; Yu, C-R; Lohani, A et al. (2007) Expression of SOCS1 and SOCS3 genes is differentially regulated in breast cancer cells in response to proinflammatory cytokine and growth factor signals. Oncogene 26:1941-8|
|Nyaga, Simon G; Jaruga, Pawel; Lohani, Althaf et al. (2007) Accumulation of oxidatively induced DNA damage in human breast cancer cell lines following treatment with hydrogen peroxide. Cell Cycle 6:1472-8|
|Nyaga, Simon G; Lohani, Althaf; Jaruga, Pawel et al. (2006) Reduced repair of 8-hydroxyguanine in the human breast cancer cell line, HCC1937. BMC Cancer 6:297|
|Mambo, Elizabeth; Nyaga, Simon G; Bohr, Vilhelm A et al. (2002) Defective repair of 8-hydroxyguanine in mitochondria of MCF-7 and MDA-MB-468 human breast cancer cell lines. Cancer Res 62:1349-55|