Telang N T, Arcuri F, Granata O M, Bradlow H L, Osborne M P, Castagnetta L
Strang Cancer Research Laboratory, The Rockefeller University, New York, USA.
Br J Cancer. 1998 May;77(10):1549-54. doi: 10.1038/bjc.1998.255.
Targeted overexpression of the c-myc oncogene induces neoplastic transformation in immortalized, non-tumorigenic mouse mammary epithelial cells (MMEC). Experiments in the present study were conducted to examine whether cellular transformation induced by c-myc oncogene is associated with altered metabolism of 17beta-oestradiol (E2). The parental, MMEC and the stable c-myc transfectant (MMEC/myc3) cell lines were compared for major oestrogen metabolic pathways, namely E2 and E1 interconversion, and C2- and C16alpha-hydroxylation by both high-pressure liquid chromatography (HPLC) analysis and the 3H release assay using specifically labelled [C2-3H]E2 or [C16alpha-3H]E2. The reductive conversion of E1 to E2 was about 14-fold and 12-fold higher than the oxidative conversion of E2 to E1 in MMEC and MMEC/myc3 cells respectively. However, in MMEC/myc3 cells, both reductive and oxidative reactions were decreased by about 32% and 12% relative to those seen in the parental MMEC cells (P = 0.0028). The extent of C16alpha-hydroxylation was increased by 164.3% (P < 0.001), with a concomitant 48.4% decrease (P < 0.001) in C2-hydroxylation in MMEC/myc3 cells; this resulted in a fourfold increase in the C16alpha/C2 hydroxylation ratio in this cell line. Thus, a persistent c-myc expression, leading to aberrant hyperproliferation in vitro and tumorigenesis in vivo, is associated with an altered oestrogen metabolism. However, it remains unclear whether this represents a result of oncogene expression/activation or is rather a consequence of phenotypic transformation of the cells.
c-myc癌基因的靶向过表达可诱导永生化、无致瘤性的小鼠乳腺上皮细胞（MMEC）发生肿瘤转化。本研究进行了实验，以检验c-myc癌基因诱导的细胞转化是否与17β-雌二醇（E2）代谢改变有关。通过高压液相色谱（HPLC）分析和使用特异性标记的[C2-3H]E2或[C16α-3H]E2的3H释放试验，比较了亲代MMEC细胞系和稳定的c-myc转染细胞系（MMEC/myc3）的主要雌激素代谢途径，即E2和E1的相互转化以及C2-和C16α-羟基化。在MMEC和MMEC/myc3细胞中，E1还原转化为E2的水平分别比E2氧化转化为E1的水平高约14倍和12倍。然而，在MMEC/myc3细胞中，相对于亲代MMEC细胞，还原反应和氧化反应分别降低了约32%和12%（P = 0.0028）。MMEC/myc3细胞中C16α-羟基化程度增加了164.3%（P < 0.001），同时C2-羟基化降低了48.4%（P < 0.001）；这导致该细胞系中C16α/C2羟基化比率增加了四倍。因此，持续的c-myc表达导致体外异常过度增殖和体内肿瘤发生，与雌激素代谢改变有关。然而，尚不清楚这是癌基因表达/激活的结果还是细胞表型转化的结果。
