EFFECTS OF ESTROGEN AND TAMOXIFEN ON THE MAP KINASE CASCADE IN EXPERIMENTAL RAT BREAST-CANCER

The mitogen-activated protein kinase (MAPK) cascade, which includes MA PK, MAP kinase kinase (MAPKK) and Raf-l, is involved in the signal tra nsduction of growth factor receptors. We found that the MAPK and Raf-l proteins are increased in human breast cancer. Activated MAPKK was al so observed. We then investigated whether the MAPK cascade is activate d when 7,12-dimethylbenz(a) anthracene (DMBA)-induced rat mammary canc er is treated with 17 beta-estradiol (E-2). Ovariectomy suppressed MAP K expression in tumors, and E-2 administration induced the activation of MAPK in ovariectomized rats. We also investigated the effects of ta moxifen (TAM) on proliferation and the MAPK cascade in DMBA-induced ra t mammary cancers. Although tumor size was reduced significantly by TA M, the expression of the MAPK and Raf-l proteins did not decrease. Add itionally, MAPK and Raf-l protein expression increased in tumors of ov ariectomized rats given TAM, despite a reduction in the size of the tu mors. These results suggest that the activated MAPK cascade is importa nt in human breast cancer, and is an important mechanism in the estrog en-dependent growth of DMBA-induced rat mammary cancer. TAM shows E-2- antagonistic effects on tumor proliferation, and E-2-agonistic effects on the MAPK cascade.