Biomedical subjects
Publications and source records attributed to V Craig Jordan.
A specific increase in the level of a single coactivator appears to enhance estrogen action with tamoxifen at some gene targets in uterine cells but not breast cells.
The groundwork for making the concept of breast cancer chemoprevention a clinical reality began over a century ago. Although tamoxifen's first clinical use was for the treatment of breast cancer, the earliest animal studies with the drug provided the scientific basis for chemoprevention. The extensive clinical experience, safety and laboratory data have made tamoxifen the current standard-of-care for the prevention of breast cancer in women at elevated risk. The STAR trial will address the value of raloxifene as a chemopreventative in postmenopausal women. Results will be available by 2005. Newer compounds are under development which hold the promise of expanded efficacy and narrower side-effect profile. These compounds will function as multifunctional medicines and will hold the promise of preventing breast and endometrial cancer, while providing the beneficial effects of preventing osteoporosis and coronary heart disease.
This review explores the recent experience with, and the basis for, the use of selective estrogen receptor modulators to treat and prevent breast cancer. As new agents are unveiled, they will continue to be tested against tamoxifen. A number of new selective estrogen receptor modulators are in clinical development in an attempt to decrease the unwanted effects of tamoxifen. Raloxifene holds the promise of treating osteoporosis with the beneficial side effect of breast cancer prevention. Additionally, two different classes of hormonal agents, the aromatase inhibitors and estrogen receptor down-regulators, which have no estrogen-like properties at any site, appear to be promising new treatments for advanced breast cancer.
This article provides an overview of the historical development, current research, clinical benefits, and potential future applications of the selective estrogen receptor modulators (SERMs), tamoxifen and raloxifene. The understanding of the mechanism of action of SERMs led not only to the development of tamoxifen, the first widely used antiestrogen for breast cancer treatment, but also to its application as a chemopreventive agent. The SERM principle of antiestrogenic actions in the breast but estrogenlike actions in bone is reviewed in clinical practice through analysis of the current applications and the potential for expanding the role of SERMs. The current view of the molecular mechanism of SERM action is summarized to identify potential target sites for future research. The clinical success of tamoxifen and raloxifene for the prevention and treatment of breast cancer and osteoporosis, respectively, has encouraged the development of a range of new agents that target breast cancer, osteoporosis, coronary heart disease, and endometrial safety.
The recognition of a new group of drugs, now named selective estrogen receptor modulators (SERMs) has revolutionized prospects for the prevention of breast cancer. New agents will continue to be tested against tamoxifen, the first SERM and an established treatment of ER positive breast cancer. Raloxifene a related SERM is used to treat and prevent osteoporosis with the potential beneficial side effect of preventing breast cancer. The Study of Tamoxifen and Raloxifene (STAR) trial will establish whether raloxifene is an improvement over tamoxifen. Most importantly, emerging information about the molecular pharmacology of SERMs will be used to decipher the mechanism of action at specific target sites around a woman's body. This knowledge can be used to design new SERMs and advance the prospects for multifunctional medicine to prevent breast cancer, osteoporosis and coronary heart disease.
PURPOSE: Cross-resistance is an important issue for the evaluation of new antiestrogens to treat advanced breast cancer patients who have failed tamoxifen therapy. In addition, postmenopausal patients treated with long-term adjuvant tamoxifen show a 3-4-fold increase in the risk of developing endometrial cancer. Consequently, a new second line agent should be more antiestrogenic and less estrogen-like on the uterus, and be effective at controlling the growth of breast cancer after exposure to tamoxifen. The purpose was to evaluate the effects of the new tamoxifen analogue GW5638 on breast and endometrial cancer growth. EXPERIMENTAL DESIGN: Athymic mice were transplanted with an endometrial tumor model (ECC-1 E2) that is responsive to estrogen and has never been exposed to antiestrogen. In addition, we used three breast tumor models: a tamoxifen-naïve tumor (T47D-E2) and two tamoxifen-stimulated tumors (MT2 TAM and MCF-7 TAM LT). The antiestrogen GW5638 (1.5 mg daily), tamoxifen (0.5 mg or 1.5 mg daily), and raloxifene (1.5 mg daily) were given p.o. The pure antiestrogen ICI182,780 (5 mg once a week) was given s.c. Western blots from MCF-7 TAM breast tumors were performed to demonstrate the regulation of estrogen receptor alpha expression by different ligands. RESULTS: Estradiol and GW5638 down-regulated the receptor compared with control. ICI182,780 completely degraded the receptor but tamoxifen had no effect. GW5638 did not promote tumor growth, and was effective in blocking the effects of postmenopausal estradiol on the growth of tamoxifen-naïve breast and endometrial tumors. However, raloxifene did not completely block the effects of postmenopausal estradiol on the growth of tamoxifen-naïve endometrial tumor after 14 weeks. GW5638 and ICI182,780 but not raloxifene were also effective in blocking the tamoxifen-stimulated breast tumor growth in athymic mice. CONCLUSIONS: GW5638 is more effective than raloxifene in blocking the effect of estrogen on tamoxifen-naïve endometrial cancer. More importantly, GW5638, like the pure antiestrogen ICI182,780, is able to block the growth of breast cancer stimulated by tamoxifen differently from raloxifene. GW5638 down-regulates estrogen receptor but does not completely destroy the receptor. Therefore, based on our findings, GW5638 could be developed as a second line agent for advanced breast cancer patients and an important first line agent to evaluate as an adjuvant treatment or chemopreventive.
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Amino acid Asp-351 in the ligand binding domain of estrogen receptor alpha (ERalpha) plays an important role in regulating the estrogen-like activity of selective estrogen receptor modulator-ERalpha complexes. 4-Hydroxytamoxifen is a full agonist at a transforming growth factor alpha target gene in situ in MDA-MB-231 human breast cancer cells stably transfected with the wild-type ERalpha. In contrast, raloxifene (Ral), which is also a selective estrogen receptor modulator, is a complete antiestrogen in this system. Because D351G ERalpha allosterically silences activation function-1 activity in the 4-hydroxytamoxifen-ERalpha complex with the complete loss of estrogen-like activity, we examined the converse interaction of amino acid 351 and the piperidine ring of the antiestrogen side chain of raloxifene to enhance estrogen-like action. MDA-MB-231 cells were either transiently or stably transfected with Asp-351 (the wild type), D351E, D351Y, or D351F ERalpha expression vectors. Profound differences in the agonist and antagonist actions of Ralcenter dotERalpha complexes were noted only in stable transfectants. The agonist activity of the Ralcenter dotERalpha complex was enhanced with D351E and D351Y ERalpha, but raloxifene lost its agonist activity with D351F ERalpha. The distance between the piperidine nitrogen of raloxifene and the negative charge of amino acid 351 was critical for estrogen-like actions. The role of the piperidine ring in neutralizing Asp-351 was addressed using compound R1h, a raloxifene derivative replacing the nitrogen on its piperidine ring with a carbon to form cyclohexane. The derivative was a potent agonist with wild type ERalpha. These results support the concept that the side chain of raloxifene shields and neutralizes the Asp-351 to produce an antiestrogenic ERalpha complex. Alteration of either the side chain or its relationship with the negative charge at amino acid 351 controls the estrogen-like action at activating function 2b of the selective estrogen receptor modulator ERalpha complex.
Endocrine therapy that targets the estrogen receptor (ER) is a standard of care for the treatment of postmenopausal women with ER-positive breast cancer. The selective ER modulator (SERM) tamoxifen has been in use for the treatment of advanced breast cancer for more than 30 years and is currently a treatment option for all stages of ER-positive disease. Tamoxifen blocks the action of estrogen by binding to the ER, and possesses both ER-agonist and antagonist properties. Unfortunately, long-term use of tamoxifen is associated with several important concerns including an increased risk of endometrial cancer and thromboembolic complications. In addition, many patients who initially respond to tamoxifen eventually relapse with resistant disease. New treatment approaches are therefore required. A number of alternative SERMs have been tested as substitutes for tamoxifen. These include; toremifene, droloxifene, idoxifene, and keoxifene. Unfortunately, the SERMs have not proved to be more effective than tamoxifen for the treatment of advanced breast cancer and have shown a high level of cross-resistance with tamoxifen. The subsequent development of the aromatase inhibitors (AIs) is an important therapeutic advance by creating a "no estrogen" environment. Another approach is the development of pure antiestrogens. Fulvestrant is a novel ER antagonist that destroys the ER and its signaling pathway and is not associated with tamoxifen-like agonist effects. It produces high response rates compared with other SERMs and is not cross-resistant to tamoxifen or aromatase inhibitors and is equally as effective as the AI anastrozole in the treatment of postmenopausal women with advanced breast cancer who have progressed on prior adjuvant tamoxifen therapy. This review article discusses the significant and continuing value of SERMs for the treatment of postmenopausal ER-positive breast cancer.