Telang N T, Kurihara H, Wong G Y, Bradlow H L, Osborne M P
Breast Cancer Research Laboratory, Memorial Sloan-Kettering Cancer Center, New York, New York 10021.
Anticancer Res. 1991 May-Jun;11(3):1021-7.
Specific and sensitive markers capable of determining the extent of tumorigenesis are important end points not only for evaluating the carcinogenic potency, but also for assessment of chemopreventive efficacy of modulators. Prototypic mammary carcinogens induce a high frequency of mammary adenocarcinomas. The appearance of tumors, however, is a culmination of initiational and promotional events whose modulation may constitute an effective means for chemopreventive interventions. The purpose of this study was i) to identify intermediate biomarkers for mammary cell transformation and ii) to apply these biomarkers and validate the ability of selected fatty acids to modulate chemical carcinogen-induced tumorigenic transformation. An in vitro model derived from mouse mammary explant cultures was utilized to examine the effects of 7,12 dimethylbenz (a) anthracene (DMBA), a prototype chemical carcinogen for rodent mammary gland. The effects of DMBA exposure were quantified at the molecular level by determining induction of oncogene expression, at metabolic level by determining the extent of estradiol metabolism, and at cellular level by determining the emergence of hormone-independent mammary alveolar lesions (MAL) and their tumorigenic potential. DMBA treatment induced binding of ras oncogene product ras p21 to [alpha 32P] GTP, altered estradiol metabolism by increasing the ratio of C16 alpha/C2 hydroxylation in favor of 16 alpha-OHE1 formation, and exhibited high frequency of MAL. Transplantation of cells from these MAL produced rapidly growing tumors. Treatment of DMBA-exposed cultures with polyunsaturated n-6 fatty acids enhanced, and treatment with polyunsaturated n-3 fatty acid suppressed the molecular, metabolic and cellular intermediate biomarkers for tumorigenic transformation. Thus, oncogene expression, estradiol metabolism and formation of MAL may constitute useful molecular, metabolic and cellular intermediate biomarkers. Alteration of these biomarkers by selected fatty acids is suggestive of their utility as end points for the chemopreventive efficacy of dietary agents.
能够确定肿瘤发生程度的特异性和敏感性标志物不仅是评估致癌潜能的重要终点，也是评估调节剂化学预防效果的重要终点。典型的乳腺致癌物可诱发高频率的乳腺腺癌。然而，肿瘤的出现是起始和促进事件的最终结果，对这些事件的调节可能构成化学预防干预的有效手段。本研究的目的是：i）识别乳腺细胞转化的中间生物标志物；ii）应用这些生物标志物并验证所选脂肪酸调节化学致癌物诱导的致瘤转化的能力。利用从小鼠乳腺外植体培养物衍生的体外模型来研究7,12-二甲基苯并（a）蒽（DMBA）（一种啮齿动物乳腺的典型化学致癌物）的作用。通过测定癌基因表达的诱导情况在分子水平上对DMBA暴露的影响进行定量，通过测定雌二醇代谢程度在代谢水平上进行定量，通过测定激素非依赖性乳腺肺泡病变（MAL）的出现及其致瘤潜能在细胞水平上进行定量。DMBA处理诱导了ras癌基因产物ras p21与[α32P]GTP的结合，通过增加C16α/C2羟基化比例以利于16α-羟基雌酮1（16α-OHE1）的形成改变了雌二醇代谢，并表现出高频率的MAL。来自这些MAL的细胞移植产生了快速生长的肿瘤。用多不饱和n-6脂肪酸处理DMBA暴露的培养物可增强致瘤转化的分子、代谢和细胞中间生物标志物，而用多不饱和n-3脂肪酸处理则可抑制这些标志物。因此，癌基因表达、雌二醇代谢和MAL的形成可能构成有用的分子、代谢和细胞中间生物标志物。所选脂肪酸对这些生物标志物的改变表明它们可作为膳食剂化学预防效果的终点。
