Department of Pathology, Wake Forest University Health Sciences, Medical Center Boulevard, Winston-Salem, NC 27157 USA.
Oncogene. 2013 Aug 29;32(35):4120-9. doi: 10.1038/onc.2012.423. Epub 2012 Oct 8.
Our recent study showed critical roles of Dmp1 as a sensor of oncogenic Ras, HER2/neu signaling and activation of the Arf-p53 pathway. To elucidate the role of human DMP1 (hDMP1) in breast cancer, one hundred and ten pairs of human breast cancer specimen were studied for the alterations of the hDMP1-ARF-Hdm2-p53 pathway with follow up of clinical outcomes. Loss of heterozygosity (LOH) of the hDMP1 locus was found in 42% of human breast carcinomas, while that of INK4a/ARF and p53 were found in 20 and 34%, respectively. Hdm2 amplification was found in 13% of the same sample, which was found independently of LOH for hDMP1. Conversely, LOH for hDMP1 was found in mutually exclusive fashion with that of INK4a/ARF and p53, and was associated with low Ki67 index and diploid karyotype. Consistently, LOH for hDMP1 was associated with luminal A category and longer relapse-free survival, while that of p53 was associated with non-luminal A and shorter survival. Thus, loss of hDMP1 could define a new disease category associated with prognosis of breast cancer patients. Human breast epithelial cells/cancer cells with wild-type p53 were sensitive to growth inhibition by activated Dmp1:ER while those that delete p14(ARF) or p53, and/or Hdm2 amplification showed partial or nearly complete resistance, indicating that p53 is a critical target for hDMP1 to exhibit its biological activity.
我们最近的研究表明，Dmp1 在作为致癌 Ras、HER2/neu 信号和 Arf-p53 通路激活的传感器方面具有关键作用。为了阐明人 DMP1（hDMP1）在乳腺癌中的作用，研究了 110 对人乳腺癌标本中 hDMP1-ARF-Hdm2-p53 通路的改变，并对临床结果进行了随访。发现 42%的人乳腺癌存在 hDMP1 基因座的杂合性丢失（LOH），而 INK4a/ARF 和 p53 的 LOH 分别为 20%和 34%。在相同的样本中发现了 13%的 Hdm2 扩增，这与 hDMP1 的 LOH 无关。相反，hDMP1 的 LOH 以与 INK4a/ARF 和 p53 相互排斥的方式出现，并且与 Ki67 指数低和二倍体核型相关。一致地，hDMP1 的 LOH 与 luminal A 类别和更长的无复发生存期相关，而 p53 的 LOH 与非 luminal A 和更短的生存期相关。因此，hDMP1 的缺失可以定义一个与乳腺癌患者预后相关的新疾病类别。野生型 p53 的人乳腺上皮细胞/癌细胞对激活的 Dmp1:ER 的生长抑制敏感，而那些缺失 p14(ARF)或 p53，和/或 Hdm2 扩增的细胞表现出部分或几乎完全耐药性，表明 p53 是 hDMP1 发挥其生物学活性的关键靶标。
