TGF-alpha exerts biphasic effects on estrogen--and phytoestrogen-mediated gene expression in breast cancer cells.
Transforming growth factor-alpha (TGF-alpha) contributes to the progression of mammary carcinogenesis in part through synergistic augmentation of estradiol (E2) action. To investigate this further, we sought to determine (1) whether the duration of TGF-alpha treatment might influence the nature of the TGF-alpha/E2 interaction, and (2) whether TGF-alpha would behave in a similar manner when combined with phytoestrogens. To this end, we transfected T47-D breast cancer cells with an estrogen-responsive reporter and then treated the cells (for 4-48 h) with varying concentrations of TGF-alpha, E2, the antiestrogen 4-hydroxy-tamoxifen (HOT), and/or one of three phytoestrogens. Our findings revealed that TGF-alpha has short-term synergistic and long-term inhibitory effects on E2- and phytoestrogen-regulated gene expression. Furthermore, this secondary inhibition of E2 action by TGF-alpha was similar in magnitude to that imposed by HOT. These findings demonstrate a novel role for TGF-alpha and invite reevaluation of current models regarding TGF-alphas interactions with E2 in breast cancer cells. Our results also raise the possibility that phytoestrogens, which interact with TGF-alpha in a manner conceptually identical to that of E2, may subserve a regulatory function in breast cancer cells.
Willard
S T
ST
Department of Cell Biology and Anatomy, Medical University of South Carolina, Charleston 29425, USA.
Frawley
L S
LS
D000230:Adenocarcinoma / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics*; D004357:Drug Synergism; D004965:Estrogen Antagonists / Q000494:pharmacology; D004967:Estrogens / Q000494:pharmacology*; D004968:Estrogens, Non-Steroidal / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D007529:Isoflavones; D008156:Luciferases / Q000378:metabolism; D048789:Phytoestrogens; D028321:Plant Preparations; D011960:Receptors, Estrogen / Q000819:agonists / Q000187:drug effects; D013629:Tamoxifen / Q000031:analogs & derivatives / Q000494:pharmacology; D014162:Transfection / Q000235:genetics; D016211:Transforming Growth Factor alpha / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D004965:Estrogen Antagonists; D004967:Estrogens; D004968:Estrogens, Non-Steroidal; D007529:Isoflavones; D048789:Phytoestrogens; D028321:Plant Preparations; D011960:Receptors, Estrogen; D016211:Transforming Growth Factor alpha; D013629:Tamoxifen; C016601:afimoxifene; D008156:Luciferases