Gynecologic effects of tamoxifen and the association with endometrial carcinoma.

Tamoxifen has been used as an adjuvant therapy for breast cancer for nearly two decades. The benefits of adjuvant tamoxifen therapy in prolonging disease-free and overall survival have been shown in randomized clinical trials. Despite this, some developing evidence suggests that tamoxifen causes a 2- to 3-fold increase in endometrial cancer.

Increasing the number of tandem estrogen response elements increases the estrogenic activity of a tamoxifen analogue.

There have been several reports of women who have tumor relapse while on tamoxifen therapy, followed by tumor regression after tamoxifen withdrawal. In such apparently tamoxifen-stimulated tumors, there is likely a genetic change which increases the estrogenicity of tamoxifen. In this study, we determine if increasing the number of estrogen response elements (EREs) in the promoter region of a reporter gene can alter the agonistic activity of fixed-ring 4-hydroxytamoxifen.

Endometrial carcinoma and tamoxifen: clearing up a controversy.

During the past 5 years, a number of case reports and clinical trial results have associated tamoxifen therapy with an increased incidence of endometrial carcinoma. A review of the literature shows that there are over 200 cases of endometrial carcinoma reported in tamoxifen-treated women. Most cases are Stage I (82%), grade 1-2 disease (80%), which is consistent with the Surveillance Epidemiology and End Results Reporting data of 74 and 79% for Stage I and grade 1-2 endometrial carcinoma.

Effects of tamoxifen administration on the expression of xenobiotic metabolizing enzymes in rat liver.

The nonsteroidal antiestrogen tamoxifen is widely used in breast cancer treatment and is currently under evaluation as a chemopreventive agent for individuals at high risk of contracting the disease. The effects of tamoxifen administration on the expression of xenobiotic metabolizing enzymes in F344 rat liver have been investigated. Tamoxifen administration for 7 days produced a dose-dependent increase in enzyme expression similar to that reported to be produced by phenobarbital.

The biological action of cDNAs from mutated estrogen receptors transfected into breast cancer cells.

While tamoxifen may inhibit breast cancer proliferation, mutations in the estrogen receptor could potentially result in breast cancer cells which can circumvent the tamoxifen blockade. Previously, we identified a mutation at codon 351 in the estrogen receptor from a tamoxifen-stimulated human breast cancer. This receptor was stably transfected into the estrogen receptor-negative human breast cancer cell line MDA-MB-231 (clone 10A).

The decreased influence of overall treatment time on the response of human breast tumor xenografts following prolongation of the potential doubling time (Tpot).

Purpose: Repopulation during fractionated radiotherapy has been postulated to result in a significant loss in local control in rapidly proliferating tumors. Clinical data suggest that accelerated fractionation schedules can overcome the influence of repopulation by limiting the overall treatment time. Unfortunately, accelerated therapy frequently leads to increased acute reactions, which may become dose limiting.

Third annual William L. McGuire Memorial Lecture. "Studies on the estrogen receptor in breast cancer"--20 years as a target for the treatment and prevention of cancer.

In 1973, McGuire and Chamness (In: O'Malley BW and Means AR (ed) Receptors for Reproductive Hormones, Plenum Press) summarized their work on the estrogen receptor in animal and human breast tumors, and in so doing described a target for therapeutic intervention. At that time there were no clinically useful antiestrogens, but the subsequent development of tamoxifen for breast cancer therapy has revolutionized the approach to treatment. Long-term adjuvant tamoxifen adjuvant therapy (i.

Alternate antiestrogens and approaches to the prevention of breast cancer.

The biological rationale and extensive clinical experience with the breast cancer drug tamoxifen make it the agent of choice for testing as a breast cancer preventive. However, concerns (Jordan and Morrow, Eur J Cancer, in press) about development of endometrial cancer in patients and liver tumors in rats with tamoxifen has encouraged the investigation of other antiestrogens. At present no compounds are available to replace tamoxifen, but two triphenylethylenes, toremifene and droloxifene, have been tested in postmenopausal women to treat advanced breast cancer.

Tamoxifen: toxicities and drug resistance during the treatment and prevention of breast cancer.

Tamoxifen, a nonsteroidal antiestrogen, is the endocrine therapy of choice for all stages of breast cancer. There are six million women-years of experience with tamoxifen, and the drug has produced survival advantages in node-positive and node-negative patients who have had 2-5 years of adjuvant tamoxifen therapy. A low incidence of side effects has been reported with tamoxifen, resulting in the proposal to use the antiestrogen as a preventive agent for breast cancer.

Transfection of human estrogen receptor (ER) cDNA into ER-negative mammalian cell lines.

Estrogen responsiveness of breast tumors can be correlated with the presence or absence of the estrogen receptor (ER). Breast cancer cells that contain ER are, in general, responsive to stimulation by estrogen both in vivo and in vitro; therefore hormonal control is possible. Breast tumors that lose the ER, and become hormone-independent are refractory to the direct effect of estrogens and antiestrogens.

Paradoxical regulation of estrogen-dependent growth factor gene expression in estrogen receptor (ER)-negative human breast cancer cells stably expressing ER.

We have previously demonstrated that transfection of estrogen receptor (ER)-negative human breast cancer MDA-MB-231 (clone 10A) cells with a sense constitutive wildtype ER expression vector regains hormonal responsiveness (Jiang and Jordan, J. Natl. Cancer Inst.

Long-term Tamoxifen Therapy for the Treatment of Breast Cancer.

Tamoxifen is a nonsteroidal antiestrogen that has become the frontline endocrine therapy for all stages of breast cancer. The drug is the only single-agent therapy that, when used in an adjuvant fashion, produces a survival advantage in postmenopausal women. Survival is longer when the estrogen receptor content of the primary tumor is higher, although receptor-poor patients still have a survival advantage from adjuvant tamoxifen equivalent to that noted with combination chemotherapy.

Tamoxifen induces hepatic aneuploidy and mitotic spindle disruption after a single in vivo administration to female Sprague-Dawley rats.

Tamoxifen has found extensive use in the treatment of all stages of human breast cancer. The efficacy of tamoxifen treatment for the prevention of second primary tumors and its chemosuppressive action in animal models have led to initiation of clinical trials to test its efficacy for prevention of this disease in women. Recently, tamoxifen has been shown to induce hepatocellular carcinomas in rats.

Effect of cadmium on estrogen receptor levels and estrogen-induced responses in human breast cancer cells.

The effects of cadmium on estrogen receptor and other estrogen-regulated genes in the human breast cancer cell line MCF-7 were studied. Treatment of MCF-7 cells with 1 microM cadmium decreased the level of estrogen receptor 58%. Cadmium induced a parallel decrease in estrogen receptor mRNA (62%).

Molecular mechanisms of antiestrogen action in breast cancer.

The success of antiestrogen therapy to treat all stages of breast cancer, and the evaluation of tamoxifen as a preventive for breast cancer in normal women, have focused attention on the molecular mechanisms of antiestrogen action and mechanisms of drug resistance. The overall goal of research is to enhance current therapies and to develop new approaches for breast cancer treatment and prevention. Recent studies show that tamoxifen and the new pure antiestrogens appear to have different mechanisms of action: tamoxifen and related compounds cause a change in the folding of the steroid binding domain that prevents gene activation whereas the pure antiestrogens cause a reduced interaction at response elements and cause a rapid loss of receptor complexes.

What do we know and what don't we know about tamoxifen in the human uterus.

Since its introduction in the early seventies, the list of indications for the use of the antiestrogen tamoxifen has been continuously expanded. Tamoxifen is now used for the treatment of metastatic breast cancer and for long-term and often indefinite administration as an adjuvant therapy. Large clinical trials in three countries are now evaluating the efficacy of tamoxifen as a preventive agent.

The estrogen receptor from a tamoxifen stimulated MCF-7 tumor variant contains a point mutation in the ligand binding domain.

The nonsteroidal antiestrogen tamoxifen (TAM) is the most commonly used endocrine treatment for all stages of breast cancer in both pre- and postmenopausal women. However, the development of resistance to the drug is common, as most patients treated with TAM eventually experience a recurrence of tumor growth. One of the potential mechanisms of treatment failure is the acquisition by the tumor of the ability to respond to TAM as a stimulatory rather than inhibitory ligand.

Characterization of tamoxifen stimulated MCF-7 tumor variants grown in athymic mice.

The non-steroidal antiestrogen tamoxifen (TAM) is successfully used to treat all stages of breast cancer in both pre- and postmenopausal women. Unfortunately, most women treated with TAM eventually develop resistant tumor recurrences which require intervention with a second-line endocrine therapy, or cytotoxic chemotherapy if the recurrence is completely endocrine insensitive. There is evidence that some recurrences may in fact be TAM stimulated.

Studies of tamoxifen as a promoter of hepatocarcinogenesis in female Fischer F344 rats.

Tamoxifen, an antiestrogen used in the treatment of breast cancer, was assessed for carcinogenic potential in the two-stage model of experimental hepatocarcinogenesis. Groups of female Fisher F344 rats were initiated with a non-necrogenic, subcarcinogenic dose of diethylnitrosamine (DEN; 10 mg/kg, po) and fed tamoxifen at a concentration of 250 mg per kg of AIN-76A diet for 6 or 15 months. The livers of these animals exhibited an increase in size and number of altered hepatic foci compared with those animals which were initiated with DEN but not exposed to tamoxifen.

4-Hydroxytamoxifen, an active metabolite of tamoxifen, does not alter the radiation sensitivity of MCF-7 breast carcinoma cells irradiated in vitro.

The effect of 4-hydroxytamoxifen (4OH-TAM), the potent anti-estrogenic metabolite of tamoxifen, on the radiosensitivity of MCF-7 cells irradiated in vitro was determined. Radiation dose response curves were generated for MCF-7 cells maintained and irradiated in phenol red-free medium containing 10(-10) M estradiol (E2) with or without 10(-7) M 4OH-TAM. Immediately after irradiation cells were transferred to medium containing 10(-10) ME2 supplemented with bovine serum to stimulate colony formation.