Action of 1,25(OH)2D3 on the cell cycle genes, cyclin D1, p21 and p27 in MCF-7 cells

1,25(OH)(2)D-3 is a known growth inhibitor and differentiation inducer of several cancer cell lines. To establish the molecular mechanism of 1,25(OH)(2)D-3 as an antiproliferating agent, its effect on proliferation and gene regulation was studied in human breast cancer MCF-7 cells. 1,25(OH)(2)D-3 inhibited cell proliferation dose dependently through G1 arrest. Cyclin D1 transcription levels decreased rapidly in 1,25(OH)(2)D-3-treated cells while protein levels only decreased after 72 h of treatment. Transcription levels of p21 and p27 were upregulated with chronologically consistent changes in cell cycle distribution. Experiments with TGF-beta neutralising antibodies revealed that the largest effect of 1,25(OH)(2)D-3 on cell proliferation is likely due to a TGF-beta independent mechanism of action. The cell cycle regulatory genes, cyclin D1 and p27, are probably involved herein as their expression was not affected by the presence of neutralising antibodies. However, upregulation of p21 was completely abrogated. Therefore, the TGF-beta signalling pathway is thought to be responsible for p21 upregulation. (C) 1998 Elsevier Science Ireland Ltd. All rights reserved.