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Differential Effects of 1,25-Dihydroxyvitamin D₃ and Tetradecanoylphorbol Acetate on Cell Cycle and Apoptosis of MCF-7 Cells and a Vitamin D₃-Resistant Variant¹

W. Alton Jones Cell Science Center, Lake Placid, New York 12946

Address all correspondence and requests for reprints to: Dr. JoEllen Welsh, Senior Scientist, W. Alton Jones Cell Science Center, 10 Old Barn Road, Lake Placid, New York 12946. E-mail: jwelsh{at}cell-science.org

1,25-Dihydroxyvitamin D₃ (1,25-(OH)₂D₃), the active form of vitamin D₃, and tetradecanoylphorbol acetate (TPA) are potent negative growth regulators of breast cancer cells. In this study, we compared the mechanism of action of these two compounds in MCF-7 cells and a vitamin D₃-resistant variant (MCF-7^D3Res). In parental MCF-7 cells, 1,25-(OH)₂D₃ induced morphological and biochemical markers of apoptosis (chromatin and nuclear matrix condensation and DNA fragmentation), whereas TPA induced growth arrest without apoptosis. Both 1,25-(OH)₂D₃ and TPA independently up-regulated the vitamin D receptor, p21, and the hypophosphorylated form of retinoblastoma (Rb) protein. The growth regulatory effects of 1,25-(OH)₂D₃ and TPA did not correlate with induction of p53 protein expression. When both compounds were added simultaneously, synergistic effects on MCF-7 cell number were observed, and cell cycle regulatory proteins were down-regulated. The MCF-7^D3Res cells, which are not sensitive to 1,25-(OH)₂D₃, were growth inhibited by TPA, and TPA partially sensitized MCF-7^D3Res cells to the growth inhibitory effects of 1,25-(OH)₂D₃. In MCF-7^D3Res cells, 1,25-(OH)₂D₃ treatment had minimal effects on p21 or Rb protein expression, whereas TPA down-regulated Rb protein and transiently up-regulated p21. These studies indicate dissociation between the pathways triggered by 1,25-(OH)₂D₃ and TPA, which mediate growth regulation in MCF-7 cells. Because both compounds induce growth arrest, but only 1,25-(OH)₂D₃ mediates apoptosis, we conclude that cell cycle arrest is not sufficient to trigger cell death of MCF-7 cells, and that 1,25-(OH)₂D₃ generates distinct signals which lead to induction of apoptosis in breast cancer cells.

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