Mnt-deficient mammary glands exhibit impaired involution and tumors with characteristics of Myc overexpression
Mnt-deficient mammary glands exhibit impaired involution and tumors with characteristics of Myc overexpression
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DOI：
10.1158/0008-5472.can-05-2683
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发表时间：
2006-06-01
期刊：
影响因子：
11.2
通讯作者：
Wynshaw-Boris, Anthony
中科院分区：
文献类型：
--
作者：
Toyo-oka, Kazuhito;Bowen, Timothy J.;Wynshaw-Boris, Anthony
原癌基因c-Myc在细胞生长和人类肿瘤的发展中起着重要作用。c-Myc与Max相互作用，Myc-Max复合物结合E-box和相关序列以激活转录。最大也与Mnt相互作用，但Mnt-Max复合物在与这些序列结合时抑制转录。MNT定位于人类染色体17p13.3，这是一个在包括乳腺肿瘤在内的各种人类肿瘤中经常缺失的区域。与Mnt作为Myc拮抗剂发挥作用的可能性一致，Mnt缺陷型成纤维细胞表现出过表达Myc的细胞的许多标志性特征，并且乳腺上皮中Mnt的条件性（Cre/Lox）失活导致腺癌。在这里，我们进一步表征乳腺组织中的Mnt条件性缺失。我们发现，Mnt的损失严重破坏乳腺退化，并导致与凋亡细胞数量减少相关的导管增生。这些发现表明乳腺组织中Mnt的缺失与Myc过表达具有相似性。我们通过使用启动子阵列分析和寡核苷酸阵列的mRNA表达分析直接测试了这一点。我们发现Mnt和c-Myc在AMTV-c-Myc转基因小鼠的肿瘤中与相似的启动子结合，并且AMTV-Cre/Mnt（KO/CKO）和AMTV-c-Myc转基因小鼠的乳腺肿瘤之间的mRNA表达模式相似。这些结果揭示了Mnt在妊娠相关乳腺发育中的重要作用，并表明在Mnt缺失的情况下乳腺肿瘤发生类似于Myc失调引起的乳腺肿瘤发生。
The proto-oncogene c-Myc plays a central role in cell growth and the development of human tumors. c-Myc interacts with Max and Myc-Max complexes bind to E-box and related sequences to activate transcription. Max also interacts with Mnt but Mnt-Max complexes repress transcription when bound to these sequences. MNT maps to human chromosome 17p13.3, a region frequently deleted in various human tumors, including mammary gland tumors. Consistent with the possibility that Mnt functions as a Myc antagonist, Mnt-deficient fibroblasts exhibit many of the hallmark characteristics of cells that overexpress Myc, and conditional (Cre/Lox) inactivation of Mnt in mammary gland epithelium leads to adenocarcinomas. Here, we further characterize mammary gland tissue following conditional deletion of Mnt in the mammary gland. We show that loss of Mnt severely disrupts mammary gland involution and leads to hyperplastic ducts associated with reduced numbers of apoptotic cells. These findings suggest that loss of Mnt in mammary tissue has similarities to Myc overexpression. We tested this directly by using promoter array analysis and mRNA expression analysis by oligonucleotide arrays. We found that Mnt and c-Myc bound to similar promoters in tumors from AMTV-c-Myc transgenic mice, and mRNA expression patterns were similar between mammary tumors from AMTV-Cre/Mnt(KO/CKO) and AMTV-c-Myc transgenic mice. These results reveal an important role for Mnt in pregnancy-associated mammary gland development and suggest that mammary gland tumorigenesis in the absence of Mnt is analogous to that caused by Myc deregulation.