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Raloxifene and tamoxifen had similar effects on these mouse models of tamoxifen-naive and tamoxifen-resistant breast and endometrial cancer. Treatment with raloxifene following 5 years of adjuvant tamoxifen may not further decrease breast cancer recurrence and may increase endometrial cancer incidence.

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As women enter the menopause, the majority suffers symptoms associated with a dramatic fall in circulating levels of 17 beta-oestradiol and oestrone. As a result, the oestrogen protective effect against coronary artery disease and osteoporosis is lost. To solve these problems, hormone replacement therapy is often used. However, there are a number of side-effects including increased risk from breast and uterine cancer that can limit compliance. New drugs, called selective oestrogen modulators (SERMs), have been developed to mimic oestrogen's effects on the liver, heart and bones but without its harmful effects on the breast and uterus. SERMs are structurally diverse compounds that bind to oestrogen receptors and elicit agonist or antagonist responses depending on the target tissue and hormonal milieu. The drugs are being used, or evaluated, for the prevention of hormone-responsive breast cancer, osteoporosis and cardiovascular disease in postmenopausal women. Tamoxifen is the endocrine treatment of choice for breast cancer, but it also has beneficial effects on bone density and serum lipids in postmenopausal women. Recently, tamoxifen was shown to decrease the risk of invasive breast cancer in women at high risk. However, tamoxifen has some stimulatory effects on the endometrium. Raloxifene is used to prevent osteoporosis and fractures. Raloxifene also lowers circulating cholesterol and the incidence of invasive breast cancer in postmenopausal women but does not stimulate the endometrium. The SERMs have evolved from mere laboratory curiosities into drugs that hold promise for preventing several major diseases associated with ageing in women.

Tamoxifen is the endocrine treatment of choice for all stages of estrogen receptor (ER)-positive breast cancer, and it is the first drug approved to reduce the incidence of breast cancer in high-risk women. Unfortunately, tamoxifen also possesses some estrogen-like effects in the uterus that cause a modest increase in the risk of endometrial cancer. GW5638 is a tamoxifen derivative with a novel carboxylic acid side chain with no uterotropic activity in the rat (Willson et al., J Med Chem, 1994, 37:1550-1552). We have compared and contrasted the actions of 4-hydroxytamoxifen (4-OHT, the active metabolite of tamoxifen) with GW7604 [the presumed metabolite of GW5638 in breast (MCF-7) and endometrial (ECC-1) cell lines in vitro]. GW7604 did not cause the growth of ECC-1 cells at any concentration (10(-11)-10(-6) M), but 4-OHT was weakly estrogen-like at low concentrations (10(-11)-10(-10) M). Compounds (10(-7) M) blocked the growth promoting action of estradiol (10(-10) M) in both ECC-1 and MCF-7 cells. Western blotting was used to show that GW7604 and raloxifene did not affect ER levels significantly, compared with controls, in MCF-7 cells; whereas the pure antiestrogen ICI182,780 decreased ER levels (P < 0.05). An assay system was used that can classify compounds into tamoxifen-like, raloxifene-like, or pure antiestrogens. The assay depends on the activation of the transforming growth factor alpha (TGFalpha) gene in situ by wild-type or D351Y mutant ER stably transfected into MDA-MB-231 cells (MacGregor-Schafer et al., Cancer Res, 1999, 59:4308-4313). GW7604 inhibited both estradiol (10(-9) M) and 4-OHT (10(-8), 10(-7) M) induction of TGFalpha in a concentration related manner (10(-9)-10(-6) M). GW7604 and raloxifene stimulated TGFalpha with the D351Y ER. In contrast, ICI 182,780 (10(-6) M) did not initiate TGFalpha and blocked the induction of TGFalpha with GW7604, raloxifene, and 4-OHT in D351Y-transfected cells. Using computer-assisted molecular models of ER complexes, we found that the antiestrogenic side chain of 4-OHT weakly interacted with the surface amino acid 351 (aspartate), but the carboxylic acid of GW7604 caused a strong repulsion of aspartate 351. We propose that GW7604 is less estrogen-like than 4-OHT, because it disrupts the surface charge around aa351 required for coactivator docking in the 4-OHT:ER complex. This charge is restored in the D351Y ER, thus converting GW7604 from an antiestrogen to an estrogen-like molecule.

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Abstract.We have previously demonstrated that prolonged treatments with raloxifene (RAL) in vitro will result in phase II RAL resistance and RAL-induced tumor growth. Clinical interest prompted us to re-examine RAL resistance in vivo, particularly the effects of long-term treatments (a decade or more) on the evolution of RAL resistance. In this study, we have addressed the question of this being a reproducible phenomenon in wild-type estrogen receptor (ER)-positive human breast cell line MCF-7. MCF-7 cells cultured under estrogen-deprived conditions in the presence of 1 μM RAL for more than a year develop RAL resistance resulting in an independent cell line, MCF7-RAL. The MCF7-RAL cells grow in response to both estradiol E 2 and RAL. Fulvestrant (FUL) blocks RAL and E 2 -mediated growth. Transplantation of MCF7-RAL cells into athymic ovariectomized mice and treatment with physiologic doses of E 2 causes early E 2 -stimulated tumor growth. In contrast, continuous treatment of implanted animals with daily oral RAL (1.5 mg daily) causes growth of small tumors within 15 weeks. Continuous re-transplantation of the tumors growing in RAL-treated mice indicated that RAL stimulated tumor growth. Tumors in the untreated mice did not grow. Bi-transplantation of MCF7-E 2 and MCF7-RAL tumors into the opposing mammary fat pads of the same ovariectomized animal demonstrated that MCF7-E 2 grew with E 2 stimulation and not with RAL. Conversely, MCF7-RAL tumors grew with RAL and not E 2 , a characteristic of phase II resistance. Established phase II resistance of MCF7-RAL tumors was confirmed following up to 7 years of serial transplantation in RAL-treated athymic mice. The ER· was retained in these tumors. The cyclical nature of RAL resistance was confirmed and extended during a 2-year evolution of the resistant phases of the MCF7-RAL tumors. The MCF7-RAL tumors that initially were inhibited by E 2 grew in the presence of E 2 and subsequently grew with either RAL or E 2 . RAL remained the major grow stimulus and RAL enhanced E 2 -stimulated growth. Subsequent transplantation of E 2 stimulated tumors and evaluations of the actions of RAL, demonstrated robust E 2 -stimulated growth that was blocked by RAL. These are the characteristics of the antiestrogenic actions of RAL on E 2 -stimulated breast cancer growth with a minor component of phase I RAL resistance. Continuous transplantation of the phase I RAL-stimulated tumors for >8 months causes reversion to phase II resistance. These data and literature reports of the cyclical nature of anti-androgen/androgen responsiveness of prostate cancer growth, illustrate the generality of the evolution of antihormonal resistance in sex steroid-sensitive target tissues.