ALTERATION OF ESTRADIOL METABOLISM IN MYC ONCOGENE-TRANSFECTED MOUSE MAMMARY EPITHELIAL-CELLS

Targeted overexpression of the c-myc oncogene induces neoplastic trans formation in immortalized, non-tumorigenic mouse mammary epithelial ce lls (MMEC), Experiments in the present study were conducted to examine whether cellular transformation induced by c-myc oncogene is associat ed with altered metabolism of 17 beta-oestradiol (E-2). The parental, MMEC and the stable c-myc transfectant (MMEC/myc(3)) cell lines were c ompared for major oestrogen metabolic pathways, namely E-2 and E-1 int erconversion, and C2- and C16 alpha-hydroxylation by both high-pressur e liquid chromatography (HPLC) analysis and the H-3 release assay usin g specifically labelled [C2-H-3]E-2 or [C16 alpha-H-3]E-2. The reducti ve conversion of E-1 to E-2 was about 14-fold and 12-fold higher than the oxidative conversion of E-2 to E-1 in MMEC and MMEC/myc(3) cells r espectively. However, in MMEC/myc(3) cells, both reductive and oxidati ve reactions were decreased by about 32% and 12% relative to those see n in the parental MMEC cells (P = 0.0028), The extent of C16 alpha-hyd roxylation was increased by 164.3% (P < 0.001), with a concomitant 48. 4% decrease (P < 0.001) in C2-hydroxylation in MMEC/myc(3), cells; thi s resulted in a fourfold increase in the C16 alpha/C2 hydroxylation ra tio in this cell line. Thus, a persistent c-myc expression, leading to aberrant hyperproliferation in vitro and tumorigenesis in vivo, is as sociated with an altered oestrogen metabolism. However, it remains unc lear whether this represents a result of oncogene expression/activatio n or is rather a consequence of phenotypic transformation of the cells .