REGULATION OF PROLACTIN RECEPTOR EXPRESSION BY THE TUMOR PROMOTING PHORBOL ESTER 12-O-TETRADECANOYLPHORBOL-13-ACETATE IN HUMAN BREAST-CANCER CELLS

In both the normal and malignant human breast, cellular sensitivity to the proliferative and differentiative activities of the lactogenic ho rmones is conferred by expression of the prolactin receptor (PRLR). Th e PRLR is regulated by steroid hormones; however, recent findings have suggested that PRLR may also be regulated by protein kinase C. To exa mine this possibility we have studied the effect of various modulators of PKC activity on PRLR binding activity and gene expression in five PRLR positive human breast cancer cell lines. Treatment with 12-O-tetr adecanoylphorbol-13-acetate (TPA), a tumour promoter and modulator of PKC activity, decreased PRLR binding activity in all cell lines examin ed. In MCF-7 cells, 10 nM TPA caused a 70% loss of PRLR mRNA after 12 h, paralleled 3 h later by a comparable loss of cell surface PRLR. Mez erein, a non-phorbol ester modulator of PKC activity and 1,2-dioctanoy l-sn-glycerol, a permeant analogue of the endogenous activator of PKC, also reduced PRLR binding activity and gene expression in a time- and concentration-dependent manner. Cycloheximide failed to abrogate the TPA-induced decline in PRLR mRNA levels, indicating that this process was not dependent upon continuing protein synthesis. No change in the stability of PRLR mRNA was observed during 24 h of TPA treatment and T PA reduced the rate of PRLR gene transcription within 3 h of treatment . These results demonstrate that modulators of PKC activity reduce PRL R binding activity and gene expression, implicating this signal transd uction pathway in PRLR regulation.