The mitogen-activated protein kinase (MAPK) cascade, which includes MAPK, MAP kinase kinase (MAPKK) and Raf-l, is involved in the signal transduction of growth factor receptors. We found that the MAPK and Raf-l proteins are increased in human breast cancer. Activated MAPKK was also observed. We then investigated whether the MAPK cascade is activated when 7,12-dimethylbenz(a) anthracene (DMBA)-induced rat mammary cancer is treated with 17 beta-estradiol (E-2). Ovariectomy suppressed MAPK expression in tumors, and E-2 administration induced the activation of MAPK in ovariectomized rats. We also investigated the effects of tamoxifen (TAM) on proliferation and the MAPK cascade in DMBA-induced rat mammary cancers. Although tumor size was reduced significantly by TAM, the expression of the MAPK and Raf-l proteins did not decrease. Additionally, MAPK and Raf-l protein expression increased in tumors of ovariectomized rats given TAM, despite a reduction in the size of the tumors. These results suggest that the activated MAPK cascade is important in human breast cancer, and is an important mechanism in the estrogen-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.

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