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.
Highlights
Sex hormones have been implicated in the development of breast cancer [1,2,3]
In the Tam + E2 group, 1.460.3 tumor nodules per tumor-bearing animal were observed while in the E2 treatment group, an average of 3.160.7 tumor nodules were present in tumor-bearing rats (Table 1)
Both ductal carcinoma in situ (DCIS) and micro-invasive cancers were present in the mammary tissue of animals from E2 and Tam + E2 group (Figure 2)
Summary
Sex hormones have been implicated in the development of breast cancer [1,2,3]. the exact mechanisms underlying the initiation and progression of estrogen-related cancers remain elusive. A number of earlier studies have shown that Tam is converted to the genotoxic epoxide, as well as 4- and 2-hydroxy metabolites via enzymatic activation either by liver cytochrome P450 monoxidase [22] or by different peroxidases [23,24]. These metabolites can bind to biologically active molecules like DNA, lipids and proteins, and are capable of inducing irreversible damage to these molecules [25]. It has previously been reported that Tam treatment for 6 months abrogates E2-induced breast cancer [26]. The lack of complete inhibition of E2-induced breast cancer by Tam may be because of the inability of Tam to prevent E2-mediated oxidant stress as is suggested by the current studies
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