title: Regulation of prolactin receptor expression by the tumour promoting phorbol ester 12-O-tetradecanoylphorbol-13-acetate in human breast cancer cells.
abstract: In both the normal and malignant human breast, cellular sensitivity to the proliferative and differentiative activities of the lactogenic hormones is conferred by expression of the prolactin receptor (PRLR). The PRLR is regulated by steroid hormones; however, recent findings have suggested that PRLR may also be regulated by protein kinase C. To examine 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-tetradecanoylphorbol-13-acetate (TPA), a tumour promoter and modulator of PKC activity, decreased PRLR binding activity in all cell lines examined. 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. Mezerein, a non-phorbol ester modulator of PKC activity and 1,2-dioctanoyl-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 TPA reduced the rate of PRLR gene transcription within 3 h of treatment. These results demonstrate that modulators of PKC activity reduce PRLR binding activity and gene expression, implicating this signal transduction pathway in PRLR regulation.
authors.affiliation: Cancer Biology Division, Garvan Institute of Medical Research, St. Vincent's Hospital, Sydney, N.S.W., Australia.
authors.forename: C J
authors.initials: CJ
authors.lastname: Ormandy
authors.forename: C S
authors.initials: CS
authors.lastname: Lee
authors.forename: P A
authors.initials: PA
authors.lastname: Kelly
authors.forename: R L
authors.initials: RL
authors.lastname: Sutherland
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002273:Carcinogens / Q000494:pharmacology; D003513:Cycloheximide / Q000494:pharmacology; D004075:Diglycerides / Q000494:pharmacology; D004224:Diterpenes; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006207:Half-Life; D006801:Humans; D011493:Protein Kinase C / Q000187:drug effects*; D012333:RNA, Messenger / Q000378:metabolism; D012334:RNA, Neoplasm / Q000187:drug effects; D011981:Receptors, Prolactin / Q000187:drug effects* / Q000235:genetics; D013729:Terpenes / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects; D014407:Tumor Cells, Cultured
chemical_list: D002273:Carcinogens; D004075:Diglycerides; D004224:Diterpenes; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D011981:Receptors, Prolactin; D013729:Terpenes; C044295:1,2-dioctanoylglycerol; C011309:mezerein; D003513:Cycloheximide; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate