Autocrine stimulation of human mammary carcinoma cell proliferation by human growth hormone.
Here we have investigated the role of autocrine production of human growth hormone (hGH) in the proliferation of mammary carcinoma cells (MCF-7) in vitro. MCF-7 cells were stably transfected with an expression plasmid encoding the hGH gene, and these cells (designated MCF-hGH) synthesized hGH in the cell and secreted hGH to the medium. For control purposes, a MCF cell line was generated (MCF-MUT) in which the start codon of the hGH gene was disabled, and these cells transcribed the hGH gene without translation to hGH protein. The MCF-hGH cell number increased at a rate significantly greater than that of MCF-MUT under serum-free conditions. Autocrine hGH also synergized with 10% serum and insulin-like growth factor-1 but not 17-beta-estradiol to increase cell number. The increased proliferation of MCF-hGH cells in both serum-free and serum-containing media could be completely abrogated by the use of the nonreceptor dimerizing hGH antagonist, hGH-G120R. Increased mitogenesis as a consequence of autocrine production of hGH was prevented by inhibition of either the p38 MAPK or p42/44 MAPK pathways. MCF-hGH cells also possessed a higher level of STAT5 (but not STATs 1 and 3) mediated transcriptional activation in both serum-free and serum-containing conditions than MCF-MUT cells. Thus we conclude that hGH can act in an autocrine/paracrine manner in human mammary carcinoma cells to promote cell proliferation and transcriptional activation.
Kaulsay
K K
KK
National University Hospital, National University of Singapore, 10 Kent Ridge Crescent, Singapore, 119260, Republic of Singapore.
Mertani
H C
HC
Törnell
J
J
Morel
G
G
Lee
K O
KO
Lobie
P E
PE
D000230:Adenocarcinoma / Q000473:pathology*; D000818:Animals; D019898:Autocrine Communication; D001940:Breast / Q000378:metabolism / Q000473:pathology*; D001943:Breast Neoplasms / Q000473:pathology*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D002455:Cell Division / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D013006:Growth Hormone / Q000031:analogs & derivatives / Q000494:pharmacology; D006727:Hormone Antagonists / Q000494:pharmacology; D019382:Human Growth Hormone / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D053613:Janus Kinase 1; D053614:Janus Kinase 2; D008894:Milk Proteins; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors; D020928:Mitogen-Activated Protein Kinases; D011505:Protein-Tyrosine Kinases / Q000096:biosynthesis; D011518:Proto-Oncogene Proteins; D011986:Receptors, Somatotropin / Q000096:biosynthesis / Q000235:genetics; D011994:Recombinant Proteins; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; D015534:Trans-Activators / Q000096:biosynthesis; D014407:Tumor Cells, Cultured; D048051:p38 Mitogen-Activated Protein Kinases
D004268:DNA-Binding Proteins; C093172:G120R protein, human; D006727:Hormone Antagonists; D008894:Milk Proteins; D011518:Proto-Oncogene Proteins; D011986:Receptors, Somatotropin; D011994:Recombinant Proteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D050799:STAT5 Transcription Factor; D015534:Trans-Activators; D019382:Human Growth Hormone; D004958:Estradiol; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone; D011505:Protein-Tyrosine Kinases; C507904:JAK1 protein, human; C507924:JAK2 protein, human; D053613:Janus Kinase 1; D053614:Janus Kinase 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases