Loss of growth inhibitory effects of retinoic acid in human breast cancer cells following long-term exposure to retinoic acid

摘要: Although retinoids are known to be inhibitory breast cancer cell growth, a key remaining question is whether they would remain effective if administered long-term. We describe here the long-term effects of all- trans retinoic acid on two oestrogen-dependent human lines MCF7 and ZR-75-1. both were growth inhibited by in short-term either absence or presence oestradiol, prolonged culture with 1 microM resulted cells acquiring resistance acid. Time courses showed that oestrogen deprivation upregulation basal non-oestrogen stimulated rate such learned grow at same without as but remained throughout. Addition steroid conditions reproducible loss response although time separable preceded oestradiol. Loss did not involve receptors, ER measured binding assay RARalpha Northern blotting. Function receptors was retained terms ability oestradiol upregulate pS2 gene expression, there reduced transiently transfected ERE- RRE-linked reporter genes. Despite accepted role IGFBP3 acid-mediated inhibition, progression occurred irrespective level IGFBP3, which high resistant cells. Measurement AP1 activity had markedly different activities, accompanied cases lost reduce activity. These results warn potential could arise treatment clinical situation echo problems endocrine resistance. It seems whatever constraints imposed these have remarkable escape from inhibition. However, delay encouraging for therapy, concentration-dependence suggests absolute manipulated dose.