Induction of PDCD4 tumor suppressor gene expression by RAR agonists, antiestrogen and HER-2/neu antagonist in breast cancer cells. Evidence for a role in apoptosis
Induction of PDCD4 tumor suppressor gene expression by RAR agonists, antiestrogen and HER-2/neu antagonist in breast cancer cells. Evidence for a role in apoptosis
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DOI：
10.1038/sj.onc.1207983
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发表时间：
2004-10-21
期刊：
影响因子：
8
通讯作者：
Samuels, HH
中科院分区：
文献类型：
--
作者：
Afonja, O;Juste, D;Samuels, HH
人类乳腺肿瘤细胞的生长是通过细胞表面生长因子受体和类固醇/甲状腺/维甲酸受体基因家族的核受体的信号来调节的。维甲酸受体(RARs)是类固醇/甲状腺激素受体基因家族的成员，是配体依赖的转录因子，在体外和体内对乳腺癌细胞具有生长抑制活性。RAR激动剂抑制许多人乳腺癌细胞系的增殖，特别是那些由雌二醇(E2)或生长因子刺激生长的细胞系。此外，RAR激动剂和合成维甲酸，如费伦替尼，已被证明可诱导恶性乳腺细胞凋亡，但不能诱导正常乳腺细胞凋亡。为了更好地。在RAR介导的抑制乳腺癌细胞生长的基因中，我们使用寡核苷酸微阵列分析来创建一个乳腺癌细胞中可能受RAR激动剂调控的基因数据库。我们发现，肿瘤抑制基因PDCD4(程序性细胞死亡4)目前被评估为化学预防的目标，在T-47D乳腺癌细胞中，RARα选择性激动剂AM580诱导了大约三倍的诱导。RAR泛激动剂和AM580，但不是维甲酸X受体(RXR)激动剂，能刺激多种维甲酸抑制的乳腺癌细胞系中PDCD4的表达。RAR激动剂不能诱导乳腺癌细胞株PDCD4的表达，而维甲酸类化合物不能抑制乳腺癌细胞的生长。我们还观察到，抗雌激素和HER-2/neu拮抗剂Herceptin(曲妥珠单抗)也能诱导T-47D细胞中PDCD4的表达，提示PDCD4可能在抑制乳腺癌细胞生长中发挥核心作用。在T-47D(ER+，RAR(+))和MDA-MB-231(ER-，RAR(-))细胞中瞬时过表达PDCD_4可导致细胞凋亡，提示PDCD_4在介导乳腺癌细胞凋亡中起一定作用。此前已报道在正常乳腺的小导管上皮细胞中有PDCD4蛋白的表达。到目前为止，还没有关于RAR激动剂、抗雌激素或HER2/neu拮抗剂诱导乳腺癌细胞PDCD4表达及其在细胞凋亡中的潜在作用的报道。
The growth of human breast tumor cells is regulated through signaling involving cell surface growth factor receptors and nuclear receptors of the steroid/thyroid/retinoid receptor gene family. Retinoic acid receptors (RARs), members of the steroid/thyroid hormone receptor gene family, are ligand-dependent transcription factors, which have in vitro and in vivo growth inhibitory activity against breast cancer cells. RAR-agonists inhibit the proliferation of many human breast cancer cell lines, particularly those whose growth is stimulated by estradiol (E2) or growth factors. Additionally, RAR-agonists and synthetic retinoids such as Ferentinide have been shown to induce apoptosis in malignant breast cells but not normal breast cells. To better de. ne the genes involved in RAR-mediated growth inhibition of breast cancer cells, we used oligonucleotide microarray analysis to create a database of genes that are potentially regulated by RAR-agonists in breast cancer cells. We found that PDCD4 (programmed cell death 4), a tumor suppressor gene presently being evaluated as a target for chemoprevention, was induced about three-fold by the RARalpha-selective agonist Am580, in T-47D breast cancer cells. RAR pan-agonists and Am580, but not retinoid X receptors (RXR)-agonists, stimulate the expression of PDCD4 in a wide variety of retinoid-inhibited breast cancer cell lines. RAR-agonists did not induce PDCD4 expression in breast cancer cell lines, which were not growth inhibited by retinoids. We also observed that antiestrogen and the HER-2/neu antagonist, Herceptin (Trastuzumab), also induced PDCD4 expression in T-47D cells, suggesting that PDCD4 may play a central role in growth inhibition in breast cancer cells. Transient overexpression of PDCD4 in T-47D (ER+, RAR(+)) and MDA-MB-231 (ER-, RAR(-)) cells resulted in apoptotic death, suggesting a role for PDCD4 in mediating apoptosis in breast cancer cells. PDCD4 protein expression has previously been reported in small ductal epithelium of normal breast. To date, there has been no report of induction of PDCD4 expression by RAR-agonists, antiestrogen or HER2/neu antagonist in breast cancer cells and its potential role in apoptosis in these cells.