Progression of human breast cancers to the metastatic state is linked to hydroxyl radical-induced DNA damage.

Abstract

Hydroxyl radical damage in metastatic tumor DNA was elucidated in women with breast cancer, and a comparison was made with nonmetastatic tumor DNA. The damage was identified by using statistical models of modified base and Fourier transform-infrared spectral data. The modified base models revealed a greater than 2-fold increase in hydroxyl radical damage in the metastatic tumor DNA compared with the nonmetastatic tumor DNA. The metastatic tumor DNA also exhibited substantially greater base diversity than the nonmetastatic DNA, and a progression of radicalinduced base damage was found to be associated with the growth of metastatic tumors. A three-dimensional plot of principal components from factor analysis, derived from infrared spectral data, also showed that the metastatic tumor DNA was substantially more diverse than the tightly grouped nonmetastatic tumor DNA. These cohesive, independently derived findings suggest that the hydroxyl radical generates DNA phenotypes with various metastatic potentials that likely contribute to the diverse physiological properties and heterogeneity characteristic of metastatic cell populations.

Tumor progression to the metastatic state involves structural modifications in DNA markedly different from those associated with primary tumor formation

“…Each point was a highly discriminating representation of an individual DNA structure in that spatially and visually close points had Ͻ3% average spectral difference over the range 1750-700 cm Ϫ1 (5). The core cluster of metastatic tumor DNA points was substantially larger than the core cluster of nonmetastatic tumor DNA points and significantly more diverse (P ϭ 0.003).…”

“…In a recent study (5), the transformation of primary breast tumors to the metastatic state was shown to involve a Ͼ2-fold increase in ⅐OH damage in DNA, as indicated by modified nucleotide base models comprising mutagenic 8-hydroxyadenine (6) and the putatively nonmutagenic ring-opened product 4,6-diamino-5-formamidopyrimidine (fapyadenine; refs. [7][8][9][10][11].…”

“…In addition, plots of the modified nucleotide base model log 10 (fapyadenine͞8-hydroxyadenine) versus the size of metastatic and nonmetastatic breast tumors revealed that the metastatic tumor DNA had significantly greater structural diversity than the nonmetastatic tumor DNA (P ϭ 0.01; ref. 5).…”

“…A significant body of evidence points to the involvement of the hydroxyl radical (⅐OH) in introducing mutagenic structures into DNA of the normal female breast, thus statistically increasing the probability of breast cancer (1)(2)(3)(4)(5). In a recent study (5), the transformation of primary breast tumors to the metastatic state was shown to involve a Ͼ2-fold increase in ⅐OH damage in DNA, as indicated by modified nucleotide base models comprising mutagenic 8-hydroxyadenine (6) and the putatively nonmutagenic ring-opened product 4,6-diamino-5-formamidopyrimidine (fapyadenine; refs.…”

Expression of the CDK inhibitor p27kip1 and oxidative DNA damage in non-neoplastic and neoplastic vulvar epithelial lesions

“…However, the observation that several carcinogens cause oxidative DNA damage, with increased 8-OHdG levels, in laboratory animals before tumor formation occurs and that tumor progression is linked to this type of damage strongly support the hypothesis that oxidative DNA base modifications play an important role in carcinogenesis. 26 To our knowledge, this is the first study investigating the expression level of 8-OHdG in multistep vulvar carcinogenesis. We observed a progressive increase in the levels of 8-OHdG from normal to VIN to invasive carcinomas (Figure 2 and Tables 1 and 2).…”