Breast Cancer Program and Systems and Computational Biology, Karmanos Cancer Institute, Wayne State University, Detroit, Michigan 48201, USA.
Cancer Res. 2010 Nov 1;70(21):8487-97. doi: 10.1158/0008-5472.CAN-10-1013. Epub 2010 Oct 12.
Amplification of the 8p11-12 region has been found in about 15% of human breast cancers and is associated with poor prognosis. Earlier, we used genomic analysis of copy number and gene expression to perform a detailed analysis of the 8p11-12 amplicon to identify candidate oncogenes in breast cancer. We identified 21 candidate genes and provided evidence that three genes, namely, LSM-1, TC-1, and BAG4, have transforming properties when overexpressed. In the present study, we systematically investigated the transforming properties of 13 newly identified 8p11-12 candidate oncogenes in vitro. WHSC1L1, DDHD2, and ERLIN2 were most potently transforming oncogenes based on the number of altered phenotypes expressed by the cells. WHSC1L1 contains a PWWP-domain that is a methyl-lysine recognition motif involved in histone code modification and epigenetic regulation of gene expression. Knockdown of WHSC1L1 in 8p11-12-amplified breast cancer cells resulted in profound loss of growth and survival of these cells. Further, we identified several WHSC1L1 target genes, one of which is iroquois homeobox 3 gene (IRX3), a member of the Iroquois homeobox transcription factor family.
8p11-12 区域的扩增在约 15%的人类乳腺癌中被发现，与预后不良有关。早些时候，我们使用拷贝数和基因表达的基因组分析对 8p11-12 扩增子进行了详细分析，以鉴定乳腺癌中的候选癌基因。我们确定了 21 个候选基因，并提供了证据表明，当过度表达时，三个基因，即 LSM-1、TC-1 和 BAG4，具有转化特性。在本研究中，我们系统地研究了 13 个新鉴定的 8p11-12 候选癌基因在体外的转化特性。基于细胞表达的改变表型的数量，WHSC1L1、DDHD2 和 ERLIN2 是最有效的转化致癌基因。WHSC1L1 含有一个 PWWP 结构域，这是一个参与组蛋白编码修饰和基因表达的表观遗传调控的甲基赖氨酸识别基序。在 8p11-12 扩增的乳腺癌细胞中敲低 WHSC1L1 导致这些细胞的生长和存活明显丧失。此外，我们鉴定了几个 WHSC1L1 的靶基因，其中一个是同源框基因 3（IRX3），它是同源盒转录因子家族的一员。
