1.1 Tamoxifen for the treatment of breast cancer Tamoxifen was originally developed with the hope of becoming a “morning after” contraceptive. During the 1960s, studies showed that tamoxifen and other anti-estrogens have a profound impact on the fertility of laboratory rats and it was believed that tamoxifen could elicit the same effects in humans. Coincidently, in humans, anti-estrogens were found to improve fertility by inducing ovulation (Jordan, 2006). The use of tamoxifen for the treatment of breast cancer became apparent when early in vitro and in vivo studies found that tamoxifen inhibited estradiol (E2) binding to estrogen receptors (ERs) in breast tissue (Jordan, 1976; Jordan & Dowse, 1976; Jordan & Koerner, 1975; Nicholson & Golder, 1975). The inhibition of ERs proved to be a significant finding as the estrogen-stimulated growth and the ovarian dependence of some breast cancers had been known since the later part of the eighteenth century (Beatson, 1896). Prior to the 1970s, and the successful development of drug-based endocrine therapies, attempts to reduce estrogen-stimulated growth of breast cancer include the surgical removal of the ovaries and/or pituitary and adrenal glands (Kennedy, 1965). Unfortunately, for years it was not known which breast tumors would respond favorably to ablative surgery, where only 30% of patients would receive a benefit (Jensen et al., 1971; Kennedy, 1965). By examining proteins from breast tumor biopsies, Jensen et al. (1971) showed that if the estrogen receptor is present, tumors will respond to ablative surgical treatment, but if absent, the tumors fail to respond. Fortunately today, endocrine-based surgical procedures for breast cancer are not necessary for most women as drug-based endocrine therapies have advanced with the use of estrogen antagonists and aromatase inhibitors. Estrogen antagonists, such as tamoxifen or fulvestrant competitively inhibit estrogen binding to ERs. Aromatase inhibitors prevent estrogen production, by inhibiting the aromatase class of enzymes, impeding the conversion of androgens to estrogens and thus reducing the bioavailability of estrogen hormones (Jordan, 1994; Mokbel, 2002). Currently tamoxifen is typically used as an adjuvant treatment option for early and advanced ER-positive (ER+) breast cancer in preand post-menopausal women (Jordan, 1994). Adjuvant treatment with tamoxifen, has significantly improved disease-free survival and reduced the number of deaths from breast cancer (Early Breast Cancer Trialists' Collaborative, 2005). Tamoxifen may also be used in the neoadjuvant setting and as a