Partial Inhibition of Estrogen-Induced Mammary Carcinogenesis in Rats by Tamoxifen: Balance between Oxidant Stress and Estrogen Responsiveness

Abstract

Epidemiological and experimental evidences strongly support the role of estrogens in breast tumor development. Both estrogen receptor (ER)-dependent and ER-independent mechanisms are implicated in estrogen-induced breast carcinogenesis. Tamoxifen, a selective estrogen receptor modulator is widely used as chemoprotectant in human breast cancer. It binds to ERs and interferes with normal binding of estrogen to ERs. In the present study, we examined the effect of long-term tamoxifen treatment in the prevention of estrogen-induced breast cancer. Female ACI rats were treated with 17β-estradiol (E2), tamoxifen or with a combination of E2 and tamoxifen for eight months. Tissue levels of oxidative stress markers 8-iso-Prostane F2α (8-isoPGF2α), superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase, and oxidative DNA damage marker 8-hydroxydeoxyguanosine (8-OHdG) were quantified in the mammary tissues of all the treatment groups and compared with age-matched controls. Levels of tamoxifen metabolizing enzymes cytochrome P450s as well as estrogen responsive genes were also quantified. At necropsy, breast tumors were detected in 44% of rats co-treated with tamoxifen+E2. No tumors were detected in the sham or tamoxifen only treatment groups whereas in the E2 only treatment group, the tumor incidence was 82%. Co-treatment with tamoxifen decreased GPx and catalase levels; did not completely inhibit E2-mediated oxidative DNA damage and estrogen-responsive genes monoamine oxygenase B1 (MaoB1) and cell death inducing DFF45 like effector C (Cidec) but differentially affected the levels of tamoxifen metabolizing enzymes. In summary, our studies suggest that although tamoxifen treatment inhibits estrogen-induced breast tumor development and increases the latency of tumor development, it does not completely abrogate breast tumor development in a rat model of estrogen-induced breast cancer. The inability of tamoxifen to completely inhibit E2-induced breast carcinogenesis may be because of increased estrogen-mediated oxidant burden.

Mechanisms of estrogen carcinogenesis: The role of E2/E1–quinone metabolites suggests new approaches to preventive intervention – A review

“…In response to E2 treatment, the mammary gland undergoes progression from ductal hyperplasia to atypical hyperplasia leading to the appearance of adenocarcinomas beginning after 16-18 weeks of treatment, with tumor incidence reaching 30-100 percent depending on E2 dose [5]. Tumor development was only partially inhibited by tamoxifen [8] suggesting a role for a non-receptor dependent process in the mechanism of E2 induced mammary tumors in this model, similar to what has been observed in the ERKO/Wnt oophrctomized mouse model. However, ACI rat E2-induced mammary tumor development was significantly reduced from an incidence of 82% to 24% by treatment with the antioxidant butylated hydroxyanisole [9].…”

Differential regulation of estrogen receptors α and β by 4-(E)-{(4-hydroxyphenylimino)-methylbenzene,1,2-diol}, a novel resveratrol analog

“…In the last few decades, two major hypotheses have been proposed to explain the carcinogenic effects of estrogens. The first hypothesis suggests that steroidal estrogens bind to their cognate receptors and stimulate proliferation in cells, thus leading to cancer progression [9, 10]. The other is the metabolic hypothesis which states that genotoxic products of 17β-estradiol (E2) metabolism lead to oxidative DNA damage and initiation of cancer [4, 7, 11–14].…”

4-(E)-{(p-tolylimino)-methylbenzene-1,2-diol}, 1 a novel resveratrol analog, differentially regulates estrogen receptors α and β in breast cancer cells

“…Resveratrol is considered a phytoestrogen since it can bind to and activate estrogen receptors (ERs) α and β [9]. The significance of ERs in breast cancer is underscored by the fact that 75% of breast cancer cases are ER-positive and depend on endogenous estrogens for tumor progression [10, 11, 12]. Since Res structurally mimics estrogens, it acts as partial agonist at both the ERs [9, 13].…”