NDF INDUCES EXPRESSION OF A NOVEL 46-KD PROTEIN IN ESTROGEN-RECEPTOR POSITIVE BREAST-CANCER CELLS

Most human breast tumors start as estrogen-dependent, but during the c ourse of the disease become refractory to hormone therapy. The transit ion of breast tumors from estrogen dependent to independent behavior m ay be regulated by autocrine and/or paracrine growth factor(s) that ar e independent of the estrogen receptor (ER). We have investigated the role(s) of NDF (neu-differentiation factor) in the biology of estrogen positive breast cancer cells by using MCF-7 cells as a model system. Treatment of MCF-7 cells with human recombinant NDF-beta 2 (NDF) inhib ited the ER expression by 70% and this was associated with growth stim ulation in an estrogen-independent manner. To explore the mechanism(s) of action of NDF in MCF-7 cells, we examined the expression of NDF-in ducible gene products. We report here that NDF stimulated the levels o f expression of a 46 kD protein (p46) (in addition to few minor protei ns) in ER positive breast cancer cells including MCF-7, T-47-D, and ZR -75-R cells but not in ER negative breast cancer cells including MDA-2 31, SK-BR-3, and MDA-468 cells. This effect of NDF was due to inductio n in the rate of synthesis of new p46. The observed NDF-mediated induc tion of p46 expression was specific as there was no such effect by epi dermal growth factor or 17-beta-estradiol, and inclusion of actinomyci n D partially inhibited the p46 induction elicited by NDF. NDF-inducib le stimulation of p46 expression was an early event (2-6 h) which prec eded the period of down-regulation of ER expression by NDF. These resu lts support the existence of NDF-responsive specific cellular pathway( s) that may regulate ER, and these interactions could play a role(s) i n hormone-independence of ER positive breast cancer cells. (C) 1996 Wi iey-Liss, Inc.