Regulation of MUC1 expression in human mammary cell lines by the c-ErbB2 and ras signaling pathways.
The MUC1 protein is a highly O-glycosylated transmembrane molecule that is expressed at the luminal surface of most glandular epithelial cells and is upregulated in carcinomas. Here, we report the effect of the activation of the c-ErbB2 --> Ras pathway on the expression of the MUC1 gene in the nontumorigenic mammary cell lines MTSV1-7 and HB2 and in the malignant cell lines T47D and ZR75. Endogenous levels of MUC1 mRNA and protein in HB2 clones permanently overexpressing c-ErbB2 or V12-H-Ras were markedly reduced compared with levels in the parental cell lines. Furthermore, in transient transfection assays, the transcription of a CAT reporter construct driven by the MUC1 promoter was inhibited when cotransfected with a c-ErbB2 or a V12-H-ras expressing vector. Transient transfections using mutant forms of the ras oncogene, and the inhibitor chemical wortmannin, indicated that the pathway activated by c-ErbB2 proceeds via activation of Ras and that the Raf and phosphoinositide 3-kinase pathways are involved. Finally, cotransfection assays using a reporter gene driven by the MUC1 promoter carrying abolishing mutations in some of the cis-acting elements showed that a GC box at -99/-91 is crucial for responsiveness to c-ErbB2 inhibition of transcription.
Scibetta
A G
AG
Imperial Cancer Resarch Fund, Breast Cancer Biology Group, Thomas Guy House, Guy's Hospital, London, UK.
Albanese
I
I
Morris
J
J
Cooper
L
L
Downward
J
J
Rowe
P P
PP
Taylor-Papadimitriou
J
J
D000730:Androstadienes / Q000494:pharmacology; D001940:Breast / Q000166:cytology / Q000378:metabolism*; D001943:Breast Neoplasms / Q000235:genetics; D002460:Cell Line; D015536:Down-Regulation; D005260:Female; D005786:Gene Expression Regulation; D017930:Genes, Reporter / Q000235:genetics; D018734:Genes, erbB-2; D011905:Genes, ras; D006801:Humans; D018396:Mucin-1 / Q000235:genetics* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011401:Promoter Regions, Genetic / Q000235:genetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics; D014162:Transfection; D014407:Tumor Cells, Cultured; D000077191:Wortmannin; D018631:ras Proteins / Q000378:metabolism*
D000730:Androstadienes; D018396:Mucin-1; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D018719:Erb-b2 Receptor Tyrosine Kinases; D011993:Recombinant Fusion Proteins; D000077191:Wortmannin; D018631:ras Proteins