Chailleux C, Giamarchi C, Morales V, Moro F, Richard-Foy H
Laboratoire de Biologie Moléculaire Eucaryote, CNRS, 118, route de Narbonne, 31062 Toulouse Cedex, France.
Ann Endocrinol (Paris). 2000 May;61(2):130-5.
Chromatin restricts the accessibility of DNA to regulatory factors; its remodeling over the regulatory regions contributes to the control of gene expression. An increasing number of evidence links defects in chromatin remodeling machinery and cancer. Our aim is to elucidate the role of chromatin structure in the control of the expression of hormone-induced genes in breast cell lines estrogen-dependent or -independent for growth. Mammary tumor growth is controlled by steroid hormones via their nuclear receptor and by growth factors via tyrosine kinase receptors. 50 % of these tumors elude to hormonal control. This limits the anti-estrogen therapy. As a model, we have analyzed in several cell lines the chromatin organization of the regulatory regions of two genes, pS2 that is associated with a good prognostic, and cathepsin D (catD) that is a bad prognostic marker. The expression of the two genes is estrogen-regulated in estrogen-dependent cell line MCF7. In contrast in the hormone-independent cell line MDA MB 231, pS2 is not expressed and catD is constitutively expressed. Within the regulatory regions of pS2 gene, we have localized two regions that undergo a hormone-dependent change in chromatin structure in MCF7 cells but not in MDA MB 231. The lack of chromatin remodeling in MDA MB 231 cells is not due to the absence of expression of the estrogen receptor in the cell line. The expression of pS2 gene can be correlated with chromatin remodeling over the regulatory regions of pS2 gene. In contrast catD regulatory regions did not display hormone-dependent changes in chromatin structure, suggesting that hormone regulation takes place within regions with a constitutively open chromatin structure.
染色质限制了DNA与调控因子的可及性；其在调控区域的重塑有助于基因表达的控制。越来越多的证据表明染色质重塑机制的缺陷与癌症有关。我们的目的是阐明染色质结构在控制雌激素依赖性或非依赖性生长的乳腺细胞系中激素诱导基因表达方面的作用。乳腺肿瘤的生长受类固醇激素通过其核受体以及生长因子通过酪氨酸激酶受体的控制。这些肿瘤中有50%逃避了激素控制。这限制了抗雌激素疗法。作为一个模型，我们在几种细胞系中分析了两个基因调控区域的染色质组织，一个是与良好预后相关的pS2基因，另一个是预后不良标志物组织蛋白酶D（catD）基因。在雌激素依赖性细胞系MCF7中，这两个基因的表达受雌激素调节。相反，在激素非依赖性细胞系MDA MB 231中，pS2不表达，catD组成性表达。在pS2基因的调控区域内，我们定位了两个区域，它们在MCF7细胞中经历了激素依赖性的染色质结构变化，但在MDA MB 231细胞中没有。MDA MB 231细胞中缺乏染色质重塑并非由于该细胞系中雌激素受体不表达。pS2基因的表达与pS2基因调控区域的染色质重塑相关。相反，catD调控区域未显示出激素依赖性的染色质结构变化，这表明激素调节发生在具有组成性开放染色质结构的区域内。
