Preclinical studies using the intratumoral aromatase model for postmenopausal breast cancer

To determine the most effective strategies for the treatment of postmenopausal hormone dependent breast cancer, we recently developed a model system in nude mice. In this model, estrogen receptor-positive human breast cancer cells (MCF-7) stably transfected with the aromatase gene are inoculated into ovariectomized, immunosuppressed (nude) mice. These cells synthesize sufficient estrogen from androgen substrate to stimulate their proliferation and the development of tumors. Moreover, estrogen secreted by the tumor cells maintains uterine weight comparable to that of the intact mouse. In the present study, we employed this model to investigate the effects of the aromatase inhibitor, letrozole (CGS 20267 [Femara]) on mammary tumor growth and on the uterus. We also used this model to predict the effects of combining two aromatase inhibitors, letrozole and anastrozole (Arimidex), with the antiestrogen tamoxifen (Nolvadex). Letrozole was found to be a highly potent inhibitor of tumor proliferation and more effective than tamoxifen. No stimulation of uterine growth was observed with the aromatase inhibitors. However, the combination of letrozole or anastrozole and tamoxifen was no more effective than either aromatase inhibitor alone. The agonistic effect of tamoxifen on the uterus was observed when it was given alone and when combined with the aromatase inhibitors. Furthermore, letrozole had the most potent antitumor activity when compared to other aromatase inhibitors and antiestrogens. No additional benefit was observed by combining these agents with tamoxifen over treatment with aromatase inhibitors alone.