Estrogen receptor α mediated induction of the transforming growth factor α gene by estradiol and 4-hydroxytamoxifen in MDA-MB-231 breast cancer cells

The selective estrogen receptor modulator, 4-hydroxytamoxifen (4-OHT) is a full agonist at the transforming growth factor (TGF) α gene in ER negative breast cancer cells stably transfected with ERα cDNA (Levenson et al., Br. J. Cancer 77 (1998) 1812-1819). E₂ and 4-OHT increase TGFα mRNA and protein in a concentration dependent manner. The responses to E₂ and 4-OHT are blocked by the pure antiestrogen ICI 182,780, which does not induce TGFα. Transfected MDA-MB-231 cells contain functional ERα but no ERβ function was detected. Neo transfected cells that did not express ERα or cells stably transfected with the DNA binding domain mutant C202R/E203V which prevents gene activation did not induce TGFα mRNA after either E₂ or 4-OHT treatment. An examination of the time course for either 10 nM E₂ or 1 μM 4-OHT for MDA-MB-231 cells stably transfected with cDNA for ERα showed increases in TGFα mRNA within 2 or 3 h respectively. Cells pretreated with cycloheximide (1 μg/ml) showed induced TGFα mRNA in response to E₂ or 4-OHT but TGFα mRNA induction was blocked by actinomycin D (1 μg/ml). We conclude that both E₂ and 4-OHT induce TGFα by direct interaction of ERα with DNA and that ERβ is not involved in the estrogen-like response to 4-OHT in the MDA-MB-231 cells.