Pacilio C, Germano D, Addeo R, Altucci L, Petrizzi V B, Cancemi M, Cicatiello L, Salzano S, Lallemand F, Michalides R J, Bresciani F, Weisz A
Istituto di Patologia Generale e Oncologia, Facoltà di Medicina e Chirurgia, Seconda Università di Napoli, Naples, Italy.
Cancer Res. 1998 Mar 1;58(5):871-6.
Cyclin D1 is a target for positive regulation by estrogens in growth-responsive cells, in which it mediates their mitogenic effects. Amplification and overexpression of the cyclin D1 gene (CCND1) might thus represent a genetic lesion inducing hormone-independent growth of transformed cells. Indeed, cyclin D1 overexpression has been found in up to 50% of primary breast cancers, and in about one-third of these cases, this is linked to amplification of the 11q13 chromosomal region, which also includes the CCND1 gene. These tumors are predominantly estrogen receptor-positive, and for this reason, these patients are often selected for adjuvant antiestrogen therapy. No information is available, however, as to whether cyclin D1 overexpression due to gene amplification might interfere with and reduce antiestrogen efficacy. This was investigated here by taking advantage of an experimental model that reproduces cyclin D1 overexpression resulting from increased CCND1 gene dosage in hormone-responsive human breast cancer cells. For this, MCF-7 cells stably transfected with a tet-inducible cyclin D1 expression vector were tested for their in vitro response to steroidal (ICI 182,780) and nonsteroidal (trans-4-hydroxytamoxifen) antiestrogens under condition of low (endogenous only) or high (exogenous) cyclin D1 levels. Results show that although cyclin D1 overexpression seems to interfere with the early cell cycle effects of antiestrogens, it does not prevent their cytostatic actions, so that growth of cyclin-overexpressing MCF-7 cells is still efficiently inhibited in vitro by these drugs.
细胞周期蛋白D1是雌激素在生长反应性细胞中正向调节的靶点，在这些细胞中它介导雌激素的促有丝分裂作用。因此，细胞周期蛋白D1基因（CCND1）的扩增和过表达可能代表一种遗传损伤，可诱导转化细胞的激素非依赖性生长。事实上，在高达50%的原发性乳腺癌中发现了细胞周期蛋白D1过表达，在其中约三分之一的病例中，这与11q13染色体区域的扩增有关，该区域也包含CCND1基因。这些肿瘤主要是雌激素受体阳性，因此，这些患者常被选择进行辅助抗雌激素治疗。然而，关于基因扩增导致的细胞周期蛋白D1过表达是否会干扰并降低抗雌激素疗效，目前尚无相关信息。本文利用一个实验模型对此进行了研究，该模型可重现激素反应性人乳腺癌细胞中因CCND1基因剂量增加而导致的细胞周期蛋白D1过表达。为此，对稳定转染了四环素诱导型细胞周期蛋白D1表达载体的MCF-7细胞在低（仅内源性）或高（外源性）细胞周期蛋白D1水平条件下对甾体类（ICI 182,780）和非甾体类（反式-4-羟基他莫昔芬）抗雌激素的体外反应进行了测试。结果表明，虽然细胞周期蛋白D1过表达似乎会干扰抗雌激素的早期细胞周期效应，但它并不能阻止其细胞生长抑制作用，因此，这些药物在体外仍能有效抑制过表达细胞周期蛋白的MCF-7细胞的生长。
