Oncostatin M induces the differentiation of breast cancer cells.
We have recently described the action of Oncostatin M (OSM) to inhibit the proliferation of breast cancer cells. In this study we examined the action of OSM on 2 breast cancer cell lines to further characterize the nature of OSM inhibition of cellular proliferation. Treatment with OSM for 6 days resulted in an approximately 2- to 5-fold decrease in cell number, which was independent of estrogen receptor status. Consistent with this, colony formation was reduced to approximately 50% when cells were exposed to OSM in primary agar cultures. Clonogenicity was further inhibited following 7 days treatment with OSM in monolayer cultures: the total number of clonogenic cells was suppressed approximately 10-fold. Analysis of cell cycle status in OSM-treated cells demonstrated a 40% reduction in the proportion of cells in S phase within 12 hr, with an increase in cells in G0/G1. After 6 days, there was a 10-fold reduction in the absolute number of cells in S phase in OSM-treated cultures. These changes were associated with striking changes in cellular morphology, including disruption of intercellular junctions and the production of lipid droplets. There was a 5-fold increase of c-fos and c-myc mRNA within 30 min of commencing treatment with OSM. In addition, in the ER positive cells there was a decrease in ER mRNA (evident within approximately 2 hr) and ER protein expression following treatment with OSM. Conversely, there was a 5-fold increase in epidermal growth factor receptor (EGFR) mRNA within 4 hr, and a 2.5-fold rise in mRNA for transforming growth factor alpha (TGF alpha). Thus, the inhibition of breast cancer cells by OSM was associated with decreased clonogenicity, a decrease in S phase cells and a variety of phenotypic changes, all consistent with the induction of differentiation.
Douglas
A M
AM
Rotary Bone Marrow Research Laboratory, Royal Melbourne Hospital, Parkville, Australia. douglas@wehi.edu.au
Grant
S L
SL
Goss
G A
GA
Clouston
D R
DR
Sutherland
R L
RL
Begley
C G
CG
D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000473:pathology*; D002452:Cell Count / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D016213:Cyclins / Q000187:drug effects / Q000235:genetics; D004268:DNA-Binding Proteins / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D016762:Genes, fos / Q000187:drug effects; D016259:Genes, myc / Q000187:drug effects; D006131:Growth Inhibitors / Q000494:pharmacology*; D006133:Growth Substances / Q000378:metabolism; D006801:Humans; D053683:Oncostatin M; D010455:Peptides / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D017978:Receptors, Growth Factor / Q000187:drug effects / Q000378:metabolism; D050796:STAT3 Transcription Factor; D015534:Trans-Activators; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014410:Tumor Stem Cell Assay
D000970:Antineoplastic Agents; D016213:Cyclins; D004268:DNA-Binding Proteins; D006131:Growth Inhibitors; D006133:Growth Substances; C508351:OSM protein, human; D010455:Peptides; D012333:RNA, Messenger; D017978:Receptors, Growth Factor; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D015534:Trans-Activators; D053683:Oncostatin M