Georgetown Lombard综合癌症中心的研究人员发现，在小鼠内，只要两个常见基因的表达有一点点调整，就能导致乳腺癌。这两个基因分别是雌激素受体α和p53，科学家们认为健康妇女体内的这两个基因能够成为生物标志物，帮助预测未来的乳腺癌风险，文章在5月15日发布的Cancer Research上。
文章的通讯作者是乔治敦大学医学中心的肿瘤学教授Priscilla A. Furth博士，第一作者是Edgar S.Díaz-Cruz博士。Furth实验室的重心是最终开发出一组检测，以便准确判定妇女在未来患上乳腺癌的风险。为了发现这些携带风险的基因和蛋白，她开发出独特的小鼠模型，在其中操作各种遗传因子，以便了解乳腺癌风险如何随时间改变。
Furth博士表示：“人们认为，这两个基因只在乳腺癌形成之后才起作用。p53在多种癌症中发现，包括乳腺癌，而大部分患有乳腺癌的妇女都有着雌激素受体过表达。人们不知道的是，这两个基因的表达水平不同，能引发细胞内变化，从而导致乳腺癌。”
在这项研究中，Díaz-Cruz和Furth开发出一个p53基因拷贝沉默的小鼠，并检测它对肿瘤形成的影响。众所周知，p53基因是非常强大的肿瘤抑制剂。在30-40%的人乳腺癌中报道有p53的改变，而这种沉默也与癌症侵袭性增加、预后差和化疗耐药性有关。
研究人员还将雌激素受体的表达调高了2倍。大约70%患有乳腺癌的妇女都呈雌激素受体阳性，意味着雌激素受体推动了细胞生长，因为它与乳腺细胞外部过量的受体结合。
这两种小鼠模型都在乳腺组织中表现出明显的癌前改变。他们随后比较了一个p53基因和两倍雌激素受体表达的变化，发现了其早期乳腺癌发展的迹象更明显。
Furth认为：“正常的乳腺组织功能需要细胞增长和细胞死亡的平衡，在这项研究中，我们发现了失调的雌激素受体和p53表达独立且共同改变了这种平衡，并改变细胞。”Furth认为负责乳腺癌发展的分子可不止这两种，但是它们比较重要，能提供早期警告甚至是预防策略。(生物谷Bioon.com)
生物谷推荐原文出处：
Cancer Research doi: 10.1158/0008-5472.CAN-09-3450
Deregulated Estrogen Receptor and p53 Heterozygosity Collaborate in the Development of Mammary Hyperplasia
Edgar S. Díaz-Cruz1 and Priscilla A. Furth1,2
Both increased estrogen receptor (ER) expression and germline disruption of one p53 allele increase breast cancer risk in women. Genetically engineered mouse models of deregulated ER expression and p53 haploinsufficiency were used to investigate similarities and differences of each genetic lesion alone and in combination on mammary preneoplasia development. Each genetic lesion independently and in combination led to development of age-dependent preneoplasia, but the highest prevalence was found in compound mice with increased ER expression coupled with p53 heterozygosity. All genetic lesions were associated with extracellular signal-regulated kinase 1/2 activation; however, only p53 heterozygous and compound mice showed increased levels of phosphorylated AKT and decreased p27 expression. The highest levels of cell proliferation were found in compound mice, but increased levels were also found with either increased ER expression or p53 heterozygosity. Mice with increased ER expression showed predicted higher levels of nuclear-localized ER, but this was attenuated in compound mice in association with a relative increase in Src phosphorylation. Parity protection was limited to p53 heterozygous mice and not found in mice with increased ER alone. In summary, increased and deregulated ER collaborates with p53 heterozygosity in increasing the risk of mammary preneoplasia development. Cancer Res; 70(10); 3965–74. ?2010 AACR.
