Estrogen receptor alpha mediated induction of the transforming growth factor alpha 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) alpha gene in ER negat ive breast cancer cells stably transfected with ER alpha cDNA (Levenson et al., Br. J. Cancer 77 (1998) 1812-1819). E-2 and 4-OHT increase TGF alpha m RNA and protein in a concentration dependent manner, The responses to E-2 a nd 4-OHT are blocked by the pure antiestrogen ICI 182,780, which does not i nduce TGF alpha. Transfected MDA-MB-231 cells contain functional ER alpha b ut no ERP function was detected. Neo transfected cells that did not express ER alpha or cells stably transfected with the DNA binding domain mutant C2 02R/E203V which prevents gene activation did not induce TGF alpha mRNA afte r either E-2 or 4-OHT treatment. An examination of the time course for eith er 10 nM E-2 or 1 muM 4-OHT for MDA-MB-231 cells stably transfected with cD NA for ER alpha showed increases in TGF alpha mRNA within 2 or 3 h respecti vely. Cells pretreated with cycloheximide (1 mug/ml) showed induced TGF alp ha mRNA in response to E-2 or 4-OHT but TGF alpha mRNA induction was blocke d by actinomycin D (14 mug/ml). We conclude that both E-2 and 4-OHT induce TGF alpha by direct interaction of ER alpha with DNA and that ER beta is no t involved in the estrogen-like response to 4-OHT in the MDA-MB-231 cells. (C) 2001 Elsevier Science Ltd. All rights reserved.