Androgen stimulates mitogen-activated protein kinase in human breast cancer cells.
The mechanisms by which androgens modulate breast cancer cell growth are largely unknown. Using cultured human PMC42 breast cancer cells, we have determined effects of the androgen R1881 on the activity of the mitogen-activated protein kinases extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and p38 kinase. R1881 did not alter JNK and p38 kinase activity, but activated ERK in a dose-dependent manner. Activation was rapid, peaking at 5 min followed by a decline to baseline after 30-60 min, and was accompanied by tyrosine phosphorylation of ERK. The androgen antagonist flutamide elevated ERK to similar levels and DNA synthesis to levels half those seen with R1881; in addition, excess flutamide lowered R1881-stimulated DNA synthesis to levels seen with flutamide alone. These findings suggest (i) that in human PMC42 breast cancer cells R1881 activates ERK through a non-genomic mechanism, (ii) that this non-genomic mechanism is equivalently activated by the androgen antagonist flutamide, and (iii) that androgen/antiandrogen effect on DNA synthesis may involve both genomic and non-genomic mechanisms. These findings may have important implications for the clinical use of such agents in breast cancer.
Zhu
X
X
Baker Medical Research Institute, Prahran, Vic., Australia.
Li
H
H
Liu
J P
JP
Funder
J W
JW
D000726:Androgen Antagonists / Q000494:pharmacology; D001943:Breast Neoplasms / Q000201:enzymology*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D004261:DNA Replication / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D005485:Flutamide / Q000494:pharmacology; D006801:Humans; D015741:Metribolone / Q000494:pharmacology*; D045165:Testosterone Congeners / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D000726:Androgen Antagonists; D045165:Testosterone Congeners; D015741:Metribolone; D005485:Flutamide; D017871:Calcium-Calmodulin-Dependent Protein Kinases