NDF induces expression of a novel 46 kD protein in estrogen receptor positive breast cancer cells

Abstract

Most human breast tumors start as estrogen‐dependent, but during the course of the disease become refractory to hormone therapy. The transition of breast tumors from estrogen dependent to independent behavior may be regulated by autocrine and/or paracrine growth factor(s) that are 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‐β2 (NDF) inhibited the ER expression by 70% and this was associated with growth stimulation in an estrogen‐independent manner. To explore the mechanism(s) of action of NDF in MCF‐7 cells, we examined the expression of NDF‐inducible gene products. We report here that NDF stimulated the levels of expression of a 46 kD protein (p46) (in addition to few minor proteins) 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‐231, SK‐BP‐3 and MDA‐468 cells. This effect of NDF was due to induction in the rate of synthesis of new p46. The observed NDF‐mediated induction of p46 expression was specific as there was no such effect by epidermal growth factor or 17‐β‐estradiol and inclusion of actinomycin D partially inhibited the p46 induction elicited by NDF. NDF‐inducible stimulation of p46 expression was an early event (2–6 h) which preceded the period of down‐regulation of ER expression by NDF. These results support the existence of NDF‐responsive specific cellular pathway(s) that may regulate ER and these interactions could play a role(s) in hormone‐independence of ER positive breast cancer cells.