Inhibition of proliferation and expression of T1 and cyclin D1 genes by thyroid hormone in mammary epithelial cells

The relationship between thyroid hormone (triiodothyronine, T-3) and breast cancer is unclear. We studied the effect of the c-erbA/TRalpha proto-oncogene encoding a functional T-3 receptor (TRalpha1), of its ligand T-3, and of its retroviral, mutated counterpart, the v-erbA oncogene, on the proliferation capacity of nontumorigenic mammary epithelial cells (EpH4). We found that EpH4 cells expressing ectopically TR (EpH4divided byTRalpha1) or v-erbA (EpH4+v-erbA) proliferated faster than parental EpH4 cells that contained low levels of endogenous TR. T-3 inhibited DNA synthesis and proliferation in EpH4 + TRalpha1 cells but not EpH4 or EpH4 + v-erbA cells. The study of cell-cycle genes showed that T3 decreased cyclin D1 RNA and protein levels in EpH4 + TRalpha1 cells. In addition, T-3 downregulated the expression of T1, a gene that is overexpressed in human breast adenocarcinomas and is induced by mitogens, serum, and several oncogenes and cytokines. Inhibition of the T1 gene by T-3 required both de novo mRNA and protein synthesis. Furthermore, T-3 abolished the induction of T1 by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate and inhibited the activity of an activation protein 1-dependent promoter (-73-Col-CAT) in EpH4 + TRalpha1 cells, suggesting that interference with activation protein 1 transcription factor plays a part in the inhibition of the T1 gene. Our results showed that T-3 reduced the proliferation of mammary epithelial cells and inhibited the expression of cyclin D1 and T1 genes. (C) 2002 Wiley-Liss, Inc.