EGF stimulates Pit-1 independent transcription of the human prolactin pituitary promoter in human breast cancer SK-BR-3 cells through its proximal AP-1 response element.
Normal and neoplastic human mammary gland cells are targets for the proliferative action of prolactin. These cells also synthesize prolactin, thereby inducing an autocrine/paracrine proliferative loop. We present the first extensive analysis of the transcriptional regulation of the human prolactin gene (hPRL) in human mammary tumor cells, SK-BR-3. We show that the pituitary promoter is functional in these cells in the absence of the pituitary-specific factor Pit-1. Expression of exogenous Pit-1 or epidermal growth factor (EGF) treatment stimulates the transfected hPRL pituitary promoter and the endogenous hPRL expression. EGF stimulation is mediated by increased synthesis of c-fos and c-jun, resulting in AP-1 binding to the proximal hPRL pituitary promoter. This regulation involves the EGF receptor, possibly ErbB2 that is highly expressed in SK-BR-3 cells, and a PI3K/JNK pathway. The stimulation of hPRL gene transcription by EGF in mammary cells may include hPRL in a complex regulatory network controlling growth of human mammary cells.
Manfroid
Isabelle
I
Laboratoire de Biologie Moléculaire et de Génie Génétique, Institut de Chimie B6, Université de Liège, B-4000 Sart-Tilman, Belgium.
Van de Weerdt
Cécile
C
Baudhuin
Ariane
A
Martial
Joseph A
JA
Muller
Marc
M
D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000172:deficiency* / Q000235:genetics; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010902:Pituitary Gland / Q000502:physiology*; D011388:Prolactin / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D012045:Regulatory Sequences, Nucleic Acid / Q000502:physiology; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism; D050817:Transcription Factor Pit-1; D014157:Transcription Factors / Q000172:deficiency* / Q000235:genetics; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; D004815:Epidermal Growth Factor; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases; D019869:Phosphatidylinositol 3-Kinases; D011388:Prolactin; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D018719:Erb-b2 Receptor Tyrosine Kinases; D018808:Transcription Factor AP-1; D050817:Transcription Factor Pit-1; D014157:Transcription Factors; C494187:POU1F1 protein, human