A molecular strategy to control tamoxifen resistant breast cancer.
Our research goal is to develop possible strategies that could have therapeutic implications for the control of breast cancer. Although tamoxifen therapy is successful for some patients, it does not provide adequate benefit for the majority, who have ER negative disease. There is also both laboratory and clinical evidence to support the position that initially responsive tumours will eventually develop resistance to tamoxifen therapy. Since the ER mechanism is the key to the successful control of tumour growth with anti-oestrogens, we have taken the strategic step of determining whether the ER will reassert growth control in breast tumour cells. We have demonstrated that this is feasible, and it might now be appropriate to plan a "gene therapy" approach to cancer control that is based on reactivation of the ER or the development of a targeted vector. Since the concept of growth control in refractory breast cancer has become a reality, there can now be enthusiasm about developing a means to achieve this therapeutic goal. Indeed, the implications for cancer therapy could be enormous. There is every reason to suppose that other types of cancer cells transfected with steroid receptor genes will respond with growth suppression to the appropriate ligand. We have further broadened our studies of anti-oestrogens to describe a laboratory model to dissect the molecular pharmacology of hormone and anti-hormone action. In practical terms, the model has provided an insight into tamoxifen stimulated growth as a mechanism of tamoxifen resistance. The pharmacology of a model compound, fixed ring 4-hydroxytamoxifen, was changed by a mutant ER. It is possible to envisage the clonal selection of cells with mutated ER or ERE that will thrive on the partial agonist actions of tamoxifen. These cells would, as is observed in the MCF-7 TAM and EnCa101 laboratory models, also respond to oestradiol stimulation. Future studies of mutant receptors in the laboratory and clinic might provide support for a novel mechanism of tamoxifen resistance. What is most encouraging, though, is the finding that the pharmacology of new pure anti-oestrogens is not affected by the mutation in the ER and that the pure anti-oestrogens can control tamoxifen stimulated growth. These observations provide additional support for the development of pure anti-oestrogens as a therapy for breast cancer. A clinically acceptable compound could be used as a therapy after tamoxifen failure or perhaps the compound may prevent the development of receptor mutants if it is used as a first line therapy.
Jiang
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SY
Department of Human Oncology, University of Wisconsin Comprehensive Cancer Center, Madison 53792.
Jordan
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VC
D001943:Breast Neoplasms / Q000188:drug therapy*; D002455:Cell Division / Q000187:drug effects; D004351:Drug Resistance / Q000502:physiology; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology; D004967:Estrogens / Q000494:pharmacology; D006801:Humans; D008954:Models, Biological; D009376:Neoplasms, Hormone-Dependent; D053284:Polyunsaturated Alkamides; D011960:Receptors, Estrogen / Q000187:drug effects; D013629:Tamoxifen / Q000031:analogs & derivatives / Q000494:pharmacology*; D014162:Transfection
D004965:Estrogen Antagonists; D004967:Estrogens; D053284:Polyunsaturated Alkamides; D011960:Receptors, Estrogen; D013629:Tamoxifen; D004958:Estradiol; C051781:ICI 164384