Induction of a novel histone deacetylase 1/c-Myc/Mnt/Max complex formation is implicated in parity-induced refractoriness to mammary carcinogenesis
Induction of a novel histone deacetylase 1/c-Myc/Mnt/Max complex formation is implicated in parity-induced refractoriness to mammary carcinogenesis
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DOI：
10.1111/j.1349-7006.2007.00689.x
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发表时间：
2008-02-01
期刊：
影响因子：
5.7
通讯作者：
Tsubura, Airo
中科院分区：
文献类型：
--
作者：
Matsuoka, Yoichiro;Fukamachi, Katsumi;Tsubura, Airo
对致癌物诱导的上皮细胞增殖增加的不敏感性是经产乳腺的一个非常重要的特征。我们发现，N-甲基-N-亚硝基脲（MNU）诱导的乳腺导管上皮细胞的增殖爆发在经产腺体中被阻断，但在年龄匹配的处女腺（AMV）中没有。MNU处理的经产乳腺中的增殖爆发的抑制与Mnt（Myc抑制剂）的上调和组蛋白脱乙酰酶1/Mnt/Max复合物的形成相一致，所述复合物意外地含有c-Myc。这些复合物在静止成纤维细胞中的Myc靶基因（如鸟氨酸脱羧酶、细胞周期蛋白D2和转化生长因子β 1基因）的启动子上形成，并在血清刺激的细胞中分解。这些结果表明，在MNU处理的经产乳腺中，复合物也可作为生长相关Myc靶点的转录抑制物发挥作用。使用化学乳腺癌模型的人c-Ha-ras转基因（Tg）大鼠，我们证实，奇偶性保护乳腺在肿瘤发生的postinitiation阶段。尽管7，12-二甲基苯并[α]蒽诱导的可触及肿瘤的发生率从AMV Tg大鼠的61.5%降低至经产动物的28.5%，但经产大鼠的早期肿瘤病变发生率与AMV大鼠相同。限制性片段长度多态性分析检测到突变的人c-Ha-ras基因在大多数正常出现的经产Tg腺体，以及在处女腺。我们建议，加速HDAC 1/c-Myc/Mnt/Max复合物的形成，以应对致癌物暴露的结果，在下调生长相关基因，导致不应性的经产乳腺癌的后起始阶段。
Refractoriness to carcinogen-induced increases in epithelial cell proliferation is a very important characteristic of parous mammary glands. We found that N-methyl-N-nitrosourea (MNU)-induced proliferative burst in the mammary ductal epithelium was blocked in parous glands but not in age-matched virgin (AMV) glands. The inhibition of the proliferative burst in MNU-treated parous mammary glands coincided with the upregulation of Mnt, a Myc-suppressor, and the formation of histone deacetylase 1/Mnt/Max complexes that unexpectedly contained c-Myc. These complexes formed on the promoters of Myc targets, such as ornithine decarboxylase, cyclin D2, and transforming growth factor beta 1 genes, in quiescent fibroblasts, and were disassembled in serum-stimulated cells. These results suggest that the complexes also function as transcription repressors of the growth-related Myc targets in MNU-treated parous mammary glands. Using the chemical mammary carcinogenesis model of human c-Ha-ras transgenic (Tg) rats, we confirmed that parity protected the mammary glands at the postinitiation phase of tumorigenesis. Although the incidence of 7,12-dimethylbenz[alpha]anthracene-induced palpable tumors was reduced from 61.5% in the AMV Tg rats to 28.5% in the parous animals, the incidence of early neoplastic lesions in the parous rats was the same as that in the AMV rats. Restriction fragment length polymorphism analysis detected mutations in the human c-Ha-ras gene in most of the normal-appearing parous Tg glands, as well as in the virgin glands. We propose that accelerated formation of HDAC1/c-Myc/Mnt/Max complexes in response to carcinogen exposure results in down-regulation of growth-related genes, leading to the refractoriness of parous mammary glands at the postinitiation phase of carcinogenesis.