Telang N T, Bradlow H L, Osborne M P
Strang-Cornell Cancer Research Laboratory, Cornell University Medical College, New York, NY 10021.
Cancer Detect Prev. 1994;18(4):313-21.
The nonsteroidal antiestrogen tamoxifen (TAM) is used to treat receptor-positive breast cancer and is now being evaluated for prophylaxis of "high-risk" population. The present study seeks to examine mechanisms that may be critical for prophylactic effects of TAM on transformation-sensitive mammary tissue. The experimental systems utilized included: in vivo rodent models for mammary tumorigenesis and in vitro cell culture models for preneoplastic transformation. In the in vivo models TAM suppressed constitutive, as well as carcinogen-induced proliferation, expression of mammary tumor virus-associated reverse transcriptase activity and decreased the incidence and frequency of mammary hyperplastic alveolar nodules. In the in vitro models TAM suppressed carcinogen-induced DNA damage, altered cellular metabolism of estradiol favoring the formation of less estrogenic catechols, and down-regulated anchorage-independent growth that is induced by ras oncogene and chemical carcinogen. Effective down-regulation of specific proliferative and metabolic biomarkers that are perturbed in mammary cell prior to tumorigenesis provides evidence that altered cellular metabolism of E2 may, in part, be responsible for antiproliferative and prophylactic properties of TAM against mammary tumorigenesis.
非甾体类抗雌激素他莫昔芬（TAM）用于治疗雌激素受体阳性乳腺癌，目前正在对“高危”人群进行预防评估。本研究旨在探讨对TAM预防转化敏感乳腺组织的作用可能至关重要的机制。所采用的实验系统包括：用于乳腺肿瘤发生的体内啮齿动物模型和用于肿瘤前转化的体外细胞培养模型。在体内模型中，TAM抑制组成性以及致癌物诱导的增殖、乳腺肿瘤病毒相关逆转录酶活性的表达，并降低乳腺增生性肺泡结节的发生率和频率。在体外模型中，TAM抑制致癌物诱导的DNA损伤，改变雌二醇的细胞代谢，有利于形成雌激素活性较低的儿茶酚，并下调由ras癌基因和化学致癌物诱导的不依赖贴壁生长。在肿瘤发生前乳腺细胞中受到干扰的特定增殖和代谢生物标志物的有效下调提供了证据，表明E2细胞代谢的改变可能部分负责TAM对乳腺肿瘤发生的抗增殖和预防特性。
