Garcia M, Derocq D, Platet N, Bonnet S, Brouillet J P, Touitou I, Rochefort H
Institut National de la Santé et de la Recherche Médicale, Unité 148 Hormones et Cancer et Université Montpellier, France.
J Steroid Biochem Mol Biol. 1997 Apr;61(1-2):11-7. doi: 10.1016/s0960-0760(96)00255-5.
Previous studies have shown that, after wild-type estrogen receptor (ER) transfection in ER-negative breast cancer cells, estradiol but not tamoxifen prevents growth, invasiveness and metastasis of these cells in mice. Because an ER mutation at position 400 converts the triphenylethylene antiestrogen, OH-tamoxifen into a full estrogen agonist, we transfected this mutated form of human ER in an ER-negative rat cancer cell line. This was aimed at inducing an inhibitory, estrogen-like response of tamoxifen in these cells. In two stable ER-positive transfectants, OH-tamoxifen inhibited cell growth and invasiveness in vitro as efficiently as estradiol. The pure antiestrogen, ICI 164,384, was not agonistic alone and antagonized estrogen action. In contrast, the three compounds were ineffective in control mock-transfected cells. When injected into ovariectomized nude mice, ER-negative mock-transfected cells formed tumours which were significantly stimulated by estradiol and inhibited by tamoxifen treatment. This indicates that estradiol and tamoxifen altered the growth of ER-negative tumours via a general effect on the host response. Surprisingly, the hormone responsiveness of ER-positive tumours developed from ER-transfected cells did not significantly differ from that of ER-negative (mock-transfected) tumours. We conclude that transfection of a mutated human estrogen receptor inhibited, through an estrogenic activity of tamoxifen, the growth and invasiveness of these cancer cells in vitro. However, the low expression of ER did not allowed us to obtain the same effect of tamoxifen in vivo.
先前的研究表明，在雌激素受体（ER）阴性的乳腺癌细胞中转染野生型ER后，雌二醇可抑制这些细胞在小鼠体内的生长、侵袭和转移，而他莫昔芬则无此作用。由于400位的ER突变可将三苯乙烯抗雌激素OH-他莫昔芬转变为完全的雌激素激动剂，因此我们在ER阴性的大鼠癌细胞系中转染了这种突变形式的人ER。目的是在这些细胞中诱导他莫昔芬产生类似雌激素的抑制反应。在两个稳定的ER阳性转染细胞系中，OH-他莫昔芬在体外抑制细胞生长和侵袭的效果与雌二醇一样有效。纯抗雌激素ICI 164,384单独使用时无激动作用，可拮抗雌激素作用。相比之下，这三种化合物对对照的mock转染细胞无效。将ER阴性的mock转染细胞注射到去卵巢的裸鼠体内后，这些细胞形成的肿瘤受到雌二醇的显著刺激，并被他莫昔芬治疗所抑制。这表明雌二醇和他莫昔芬通过对宿主反应的总体影响改变了ER阴性肿瘤的生长。令人惊讶的是，由ER转染细胞形成的ER阳性肿瘤的激素反应性与ER阴性（mock转染）肿瘤的激素反应性没有显著差异。我们得出结论，转染突变的人雌激素受体通过他莫昔芬的雌激素活性，在体外抑制了这些癌细胞的生长和侵袭。然而，ER的低表达使我们无法在体内获得他莫昔芬的相同效果。
