Programmed Cell Death during Regression of the MCF-7 Human Breast Cancer following Estrogen Ablation

To study the mechanism of regression of human mammary cancer following estrogen ablation, estrogen-responsive MCF-7 human mam mary adenocarcinoma cells were inoculated into ovariectomized female nude mice supplemented with exogenous 17/8-estradiol (1. â€v¢i)a an I-'. implant. Implants were then removed when MCF-7 tumors were 400 nun' in size. Removal of the \-'.: implants resulted in a 50% tumor regression by 2 weeks following. tion. Associated with this regres sion is a rapid (i.e., within 1 day following E2ablation) enhanced expres sion of the transforming growth factor 0, and TRPM-2 genes, two genes the expression of which has been previously demonstrated to be enhanced in a variety of cell types induced to undergo programmed cell death (i.e., apoptosis). The enhanced expression of transforming growth factor,. -/, and TRPM-2 is not a nonspecific response since the expression of other genes, like c-fos, c-ll-ras, and pS2, decrease following I.- ablation. Fragmentation of tumor DIVAinto nucleosomal oligomers and histological appearance of apoptotic bodies are characteristic early events that precede the dramatic reduction in tumor volume following I-'.-ablation. These results demonstrate that the regression of MCF-7 human mam mary cancers in nude mice following estrogen ablation is due to a sequence of biochemical and morphological changes that result in both the cessa tion of cell proliferation and activation of programmed death or apoptosis of these MCF-7 cancer cells. Clarification of the biochemical pathway involved in the activation of this programmed cell death should identify new targets of therapy for even estrogen-independent human mammary cancer cells.