|Budget Amount *help
¥2,100,000 (Direct Cost : ¥2,100,000)
Fiscal Year 1994 : ¥500,000 (Direct Cost : ¥500,000)
Fiscal Year 1993 : ¥1,600,000 (Direct Cost : ¥1,600,000)
HEC-59 human endometrial cancer cells and MCF-7 human breast cancer cells exhibit aro aromatase activity and possess estrogen receptor (ER). With these cell lines, we studied the interaction between estrogen-dependent and estrogen-independent growth, and the effects of aromatase inhibitors to clarify the growth mechanism of estrogen-dependent cancer.
Transforming growth factor-alpha(TGF-alpha) and insulin-like growth factor-I (IGF-I) stimulated [^3H] thymidine incorporation into these cells. Estradiol (E^2) and testosterone (T,after being converted to estrogen by aromatase) stimulated [^3H] thymidine incorporation, and TGF-alpha and IGF-I modified the estrogen-dependent growth by aromatase.
After preincubation with mechanism-based inhibitors (4-hydroxyandrostenedione, 14 alpha-hydroxy-4-androstene-3,6,17-trione), aromatase activities in both cell lines were suppressed, whereas after preincubation with competitive inhibitors (aminoglutethimide, CGS16949) in MCF-7 cells it was increased. Preincubation with competitive inhibitors augmented subsequent androgen-stimulated [^3H] thymidine incorporation, while preincubation with mechanism-based inhibitors diminished the stimulation. These findings suggest that competitive inhibitors induce aromatase and accelerate subsequent androgen stimulation.
The present results suggest the presence of autoregulation system between estrogen-dependent and estrogen-independent growth channels in MCF-7 cells. To inhibit estrogen-dependent growth via aromatase activity, mechanism-based aromatase inhibitors may be more effective than competitive inhibitors.