Ospemifene inhibits the growth of dimethylbenzanthracene-induced mammary tumors in Sencar mice

Abstract

Ospemifene is a new selective estrogen receptor modulator (SERM) that is being developed for the treatment of urogenital atrophy and osteoporosis. Similarly to other SERMs, ospemifene exhibits antiestrogenic effects in breast tissue, which led to the hypothesis that it may be a potential breast cancer chemopreventive agent. We first assessed the ability of ospemifene, compared to tamoxifen and raloxifene, to prevent dimethylbenzanthracene (DMBA)-induced mammary tumors in female Sencar mice. Ospemifene (N = 18), tamoxifen (N = 20) and raloxifene (N = 17), each dosed at 50 mg/kg, were administered daily by oral gavage, in combination with 20 μg DMBA for the first 6 weeks. Control mice (N = 21) received vehicle plus DMBA only for the first 6 weeks. Daily treatment then continued for 37 weeks. As hypothesized, ospemifene greatly reduced the incidence of mammary carcinomas compared to control mice (p = 0.003), similar to tamoxifen (p = 0.0004); however, in the raloxifene group, no significant effect was seen in mammary tumor prevention (p = 0.20). A follow-up study comparing ospemifene (N = 20) to tamoxifen (N = 20) in the same model was then performed to confirm the results of the first study. The results of the follow-up study, which extended the treatment to 52 weeks, confirmed the results of our previous study, with ospemifene (p = 0.01) and tamoxifen (p = 0.004) significantly decreasing mammary carcinomas compared to controls. The results of these two studies suggest that women taking ospemifene for osteoporosis and/or urogenital atrophy may further benefit from ospemifene's breast cancer chemopreventive effects.

Introduction

Selective estrogen receptor modulators (SERMs) are a unique class of compounds that induce structural changes in the estrogen receptor (ER), which lead to either an estrogen agonistic response or an estrogen antagonistic response, depending both on the target tissue and the pharmacological activity of a particular SERM [1], [2], [3], [4]. The goal in SERM development, especially for prophylactic use in healthy women, is to design a compound with specific target tissue activity, which would optimize the beneficial effects of the drug and minimize the adverse effects. For example, the ideal SERM would have ER antagonistic effects on breast tissue while having estrogenic or agonistic effects on bone and the cardiovascular system, and neutral effects on the endometrium. The activity of SERMs is thought to be regulated through two ERs, ER-α and ER-β. The ligands, or SERMs, diffuse into the cell and bind to either ER-α or -β, causing a conformational change, which results in receptor dimerization. This promotes the interaction of the receptor with the promoter regions of the DNA, causing either a transcriptional activation or repression of estrogen target genes [5].

Tamoxifen, the first clinically useful SERM, is a triphenylethylene (Fig. 1) that has been used for the treatment of breast cancer for over 25 years [6], [7], [8], [9]. As a result of tamoxifen's clinical activity in breast cancer, the National Surgical Adjuvant Breast and Bowel Project's (NSABP) Breast Cancer Prevention Trial was initiated to evaluate tamoxifen as a chemopreventive agent. The trial showed tamoxifen reduced the risk of invasive breast cancer by 49% and noninvasive breast cancer by 50%, ultimately resulting in FDA approval of tamoxifen for reducing the risk of breast cancer in women at high risk of developing the disease [10], [11].

Raloxifene is a benzothiophene SERM (Fig. 1) that has been approved for the treatment and prevention of osteoporosis, and similar to tamoxifen, is associated with several adverse effects including hot flashes, leg cramps, influenza-like symptoms and thromboembolic events [12], [13]. However, unlike tamoxifen, it has not been associated with an increased risk of endometrial cancer, which is most likely a result of its clinically insignificant effects in the endometrium [12]. Though raloxifene is approved to treat osteoporosis, it is now being evaluated for chemopreventive effects on breast cancer as a result of its antiestrogenic activity in breast tissue [12].

Ospemifene, a triphenylethylene compound, is currently in phase III trials for the treatment of urogenital atrophy and secondarily for the prevention of osteoporosis (Fig. 1) [14], [15]. Phases I and II trials have demonstrated that ospemifene is well tolerated in healthy postmenopausal women [15], [16], [17], [18]. Though it has primarily been studied for its effects on improving bone mass and inhibiting bone loss, ospemifene has also been shown to have antiestrogenic effects on breast tissue [14]. Ospemifene appears to have few clinically significant side effects. Unlike tamoxifen which acts as an estrogen agonist in endometrial tissue, ospemifene has been shown to have neutral effects in the endometrium at clinically relevant doses [15], [16], [17]. Ospemifene treatment does not result in a high incidence of side effects commonly associated with tamoxifen and raloxifene, such as hot flashes, insomnia [15], [16], [17], nervousness, dizziness, melancholy, weakness, joint or muscle pain, headache, breast tenderness or skin itch [17]. Ospemifene also has a significant estrogenic effect in vaginal tissue [15], [17], and unlike other SERMs, does not cause vaginal dryness [15], [16]. Furthermore, to date, no thromboembolic complications have been reported [16], which is a common fear among patients receiving hormonal therapies. With the decline in hormone replacement therapy (HRT) use following the report from the Women's Health Initiative (WHI) study that HRT increases the incidence of breast cancer [19], ospemifene may also provide an alternative to postmenopausal women seeking hormonal therapies. Given the overall tolerability of ospemifene and its antiestrogenic effects in breast tissue, it is important to determine whether ospemifene may be a good candidate for breast cancer chemoprevention.