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Sensitivity and insensitivity of breast cancer to tamoxifen
D F Gibson1, M M Gottardis, V C Jordan
1Department of Human Oncology, University of Wisconsin-Madison 53792.
Abstract:
Tamoxifen is the endocrine treatment of choice for breast cancer. In several laboratory models in vivo tamoxifen is a tumoristatic agent. When MCF-7 breast cancer cells are inoculated into athymic mice, palpable tumors do not grow unless the animals are treated with estrogen, and tamoxifen inhibits estrogen-stimulated growth. If tamoxifen is stopped, tumors regrow. These results suggest that adjuvant tamoxifen therapy should involve long treatment periods (even lifetime) to prevent tumor recurrence. Unfortunately resistance to therapy and patient relapse inevitably occur, and such disease recurrence involving tamoxifen resistance is difficult to treat successfully. A laboratory model of endocrine therapy failure has been developed. When athymic mice with MCF-7 tumors are treated for 6-8 months with tamoxifen, several tumors grew and continued to grow in tamoxifen-treated mice. These estrogen receptor-positive tumors grow with either tamoxifen or estradiol. Tamoxifen-stimulated tumor growth has been observed in human endometrial tumors implanted into athymic animals. Growth of these tamoxifen-stimulated tumors can be inhibited with the pure antiestrogen ICI 164,384 upon withdrawal of tamoxifen. These data are discussed in terms of treatment strategies for tamoxifen-failed patients.
Insights
Tamoxifen therapy for breast cancer can lead to resistance and tumor regrowth. A new model shows tamoxifen can stimulate tumor growth, suggesting new treatment strategies for resistant breast cancer patients.
Area of Science:
- Endocrinology
- Oncology
- Pharmacology
Background:
- Tamoxifen is a primary endocrine therapy for breast cancer, acting as a tumoristatic agent by inhibiting estrogen-stimulated growth.
- Tumor recurrence and resistance to tamoxifen therapy are significant clinical challenges, necessitating long-term treatment and alternative strategies.
- Existing laboratory models show tamoxifen inhibits estrogen-dependent growth, but a model for tamoxifen resistance and stimulation is needed.
Purpose of the Study:
- To develop and characterize a laboratory model of endocrine therapy failure in breast cancer.
- To investigate tamoxifen's role in promoting tumor growth in resistant models.
- To explore potential therapeutic interventions for tamoxifen-resistant breast cancer.
Main Methods:
- Utilizing athymic mice inoculated with MCF-7 breast cancer cells or human endometrial tumors.
- Administering tamoxifen and estrogen to assess tumor growth dynamics.
- Evaluating the efficacy of the pure antiestrogen ICI 164,384 in inhibiting tamoxifen-stimulated tumors.
Main Results:
- Prolonged tamoxifen treatment (6-8 months) in mice led to the development of tamoxifen-resistant tumors that continued to grow.
- These resistant, estrogen receptor-positive tumors exhibited growth in the presence of both tamoxifen and estradiol.
- Tamoxifen-stimulated endometrial tumor growth was observed and subsequently inhibited by ICI 164,384 after tamoxifen withdrawal.
Conclusions:
- A novel laboratory model effectively demonstrates tamoxifen resistance and tamoxifen-stimulated tumor growth.
- These findings highlight the potential for tamoxifen to paradoxically promote tumor growth in certain contexts.
- The study suggests that pure antiestrogens like ICI 164,384 may offer therapeutic benefits for patients who have failed tamoxifen therapy.