Rochefort H, Borgna J L, Evans E
J Steroid Biochem. 1983 Jul;19(1A):69-74.
The mechanism of action of tamoxifen and of 4-hydroxytamoxifen is reviewed at the cellular and molecular level, through the current view of the authors. Synthetic antiestrogens are mainly acting directly on breast cancer cells by interacting with the estrogen receptor (RE). They prevent estrogen action by competing with estrogens on the cytosol RE. The resulting complex is partially activated, leading to its nuclear localisation and a partial and dissociated stimulation of the expression of estrogen responsive genes. A defective and partial activation of RE induced by antiestrogen is shown in vitro by several alterations of the RE concerning the dissociation rate of ligands and the affinity for double-stranded DNA and for a monoclonal antibody against the RE. The explanation of the inhibition of tumor growth is more controversial, since the proliferation of estrogen responsive cells is not only regulated by estrogens but also by other hormones and factors. We present evidence of a direct effect of antiestrogen mediated by the RE, and discuss the mechanism of resistance to antiestrogen in RE positive breast cancer cells.
本文作者从细胞和分子水平的当前观点出发，对他莫昔芬和4-羟基他莫昔芬的作用机制进行了综述。合成抗雌激素主要通过与雌激素受体（RE）相互作用直接作用于乳腺癌细胞。它们通过在细胞质RE上与雌激素竞争来阻止雌激素的作用。由此产生的复合物被部分激活，导致其核定位以及对雌激素反应性基因表达的部分和分离的刺激。抗雌激素诱导的RE的缺陷性和部分激活在体外通过RE的几种改变得以显示，这些改变涉及配体的解离速率、对双链DNA的亲和力以及对针对RE的单克隆抗体的亲和力。肿瘤生长抑制的解释更具争议性，因为雌激素反应性细胞的增殖不仅受雌激素调节，还受其他激素和因子调节。我们提供了由RE介导的抗雌激素直接作用的证据，并讨论了RE阳性乳腺癌细胞中抗雌激素耐药的机制。
