Abstract 5543: Partial inhibition of estrogen-induced breast cancer by tamoxifen in female ACI rats: Implications of oxidant stress
Authors: Singh Bhupendra , Bhat Hari K. 
Published: June 2012

Abstract
Epidemiological and experimental evidence strongly supports the role of estrogens in the etiology of breast cancer. Both estrogen receptor [ER]-dependent and ER-independent mechanisms are implicated in estrogen-induced breast carcinogenesis. Tamoxifen, a selective ER modulator is widely used as chemoprotectant in human breast cancer. It binds to ERs and interferes with normal binding of estrogen to ER and the resultant ER-dependent processes. Tamoxifen treatment for six months has previously been reported to result in complete abrogation of 17β-estradiol (E2)-induced breast cancer in female ACI rats. We investigated the effect of tamoxifen on breast tumor incidence in female ACI rats after treatment with tamoxifen for 8 months. Female ACI rats were treated with E2 (3 mg pellet, s.c.), tamoxifen (40 mg pellet, s.c.) or with a combination of E2 and tamoxifen. At the time of surgery, breast tumors were detected in the 44% of rats co-treated with tamoxifen + E2 compared to 82% in rats treated with E2 alone. The tumors were confirmed as breast adenocarcinomas by histopathological examination of paraffin-embedded tissues. Immunohistochemical and real time-PCR analysis indicated increased expression of ER-α and progesterone receptor in E2-treated mammary tissue compared to age-matched controls and inhibition of these receptors in the mammary tissue of tamoxifen-treated groups. Cytochrome P450 3A4 (CYP 3A4), and CYP 2D6, the main enzymes involved in tamoxifen metabolism were unchanged in the mammary tissue of all the treatment groups compared to controls. Tissue levels of oxidative stress markers were quantified in the mammary tissues of rats. Superoxide dismutase 2, catalase and glutathione peroxidase expressions were differentially altered in E2, tamoxifen and tamoxifen + E2 co-treated groups compared to age-matched controls. Co-treatment with tamoxifen did not decrease E2-mediated increases in 8-iso-prostane F2α levels, a marker of lipid peroxidation/oxidative stress. Oxidative stress-mediated DNA damage marker, 8-hydroxydeoxyguanosine, was quantified in the mammary tissues of all the treatment groups. Co-treatment of tamoxifen with E2 did not inhibit E2-mediated increase in 8-hydroxydeoxyguanosine levels in mammary tissue.
In summary, our studies suggest that inhibition of ER-mediated processes by tamoxifen does not completely abrogate estrogen-dependent breast tumor development in a rat model of estrogen-induced breast cancer. Our results further demonstrate that tamoxifen does not decrease E2-mediated oxidant stress and DNA damage. Thus, chronic exposure to estrogen-mediated oxidative stress may contribute to the development of breast cancer in rats co-treated with E2 and tamoxifen.
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 5543. doi:10.1158/1538-7445.AM2011-5543