Abstract 5571: Effects of fish oil and Tamoxifen on preneoplastic lesion development and biomarkers of oxidative stress in the early stages of N-methyl-N-nitrosourea-induced rat mammary carcinogenesis

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Our laboratories are interested in testing the value of combining omega-3 fatty acids and antiestrogens as a safe and effective chemopreventive strategy for breast cancer. We have shown that a fish oil rich diet (FO) (17% FO + 3% corn oil [CO]) enhances the chemopreventive action of Tamoxifen (Tam) in a prepubertal model of N-methyl-N-nitrosourea (MNU)-induced rat mammary carcinogenesis (A. Manni, et al., Cancer Prev Res 3:322, 2010). To gain insight into mechanisms of prevention and the importance of different ratios of n-3:n-6 fatty acids in inhibiting carcinogenesis, we tested the effects of two FO rich diets (17% FO + 3% CO and 10% FO + 10% CO) individually and in combination with Tam on the histologic progression of preneoplastic lesions, indices of proliferation and apoptosis, as well as expression of multiple mammary gland specific and systemic biomarkers of oxidative stress in carcinogen treated rats. Following MNU administration at 21 days of age, separate groups of rats within each experimental arm were sacrificed 24 hours, 21 days, 28 days and 35 days prior to the development of palpable tumors. Increasing the amount of FO in the diet progressively increased the n-3:n-6 ratio in the plasma from 0.13 (20% CO) to 0.38 (10% FO) and 0.96 (17% FO). Although the FO rich diets significantly reduced Ki67 expression in hyperplastic lesions in a dose-dependent fashion (17% FO > 10% FO), neither the diets nor Tam decreased the development of preneoplastic lesions indicating that the inhibitory effect on carcinogenesis results from blocking the transition from hyperplasia to adenocarcinoma, consistent with our recent published study. Dietary FO and/or Tam did not have major effects on systemic oxidative stress biomarkers (plasma protein carbonyls and blood protein bound GSH) or mammary specific biomarkers of oxidative stress, based on oxidative damage to DNA measured as 8-hydroxy-2’-deoxyguanosine (8-OH-dG) and lipid peroxidation assessed as thiobarbituric-acid reactive substances (TBARS). On the other hand, tissue levels of 8-isoprostanes, prostaglandin-like compounds formed by non-enzymatic oxidation of arachidonic acid in the cell membrane, were markedly reduced by both FO rich diets at all time points (p<0.0001). In conclusion, these results, together with our previous findings, suggest that Tam, either alone or in combination with FO, exerts its protective effects on mammary carcinogenesis by blocking the transition from hyperplasia to carcinoma. The effects of FO may be due to changes in arachidonic acid specific pathways but do not involve early changes in levels of select oxidative stress markers examined in this experimental system. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5571. doi:10.1158/1538-7445.AM2011-5571