CYCLOSPORINE-A POTENTIATES ESTRADIOL-INDUCED EXPRESSION OF THE CATHEPSIN-D GENE IN MCF7 BREAST-CANCER CELLS

Although the physiological role of the immunophilins cyclophilin-40 an d FKBP52 is unknown, their identification as components of the unactiv ated estrogen receptor has raised the possibility that they might infl uence receptor activity in response to the binding of immunosuppressan ts cyclosporin A and FK506, respectively. We have used Northern analys is to determine the influence of cyclosporin A on the expression of th e estrogen-inducible cathepsin D gene in human MCF7 breast cancer cell s. We report that 1-3 mu M cyclosporin A can potentiate cathepsin D mR NA expression by up to 2-fold in cells treated with 10(-12) to 10(-10) M estradiol. A decreased potentiation effect was noted at higher horm one concentrations. Cyclosporin A alone was unable to induce cathepsin D expression and the increased gene activation observed with combined estradiol/cyclosporin A treatment was negated by the antiestrogen ICI 164,384. Our results suggest that the increased potency of estradiol in the presence of cyclosporin A is associated with an enhanced transc riptional activity of the estrogen receptor and support a role for rec eptor-associated cyclophilin-40 in the activation process. (C) 1996 Ac ademic Press, Inc.