Georgetown Lombard綜合癌癥中心的研究人員發(fā)現(xiàn),，在小鼠內(nèi),，只要兩個常見基因的表達(dá)有一點點調(diào)整，就能導(dǎo)致乳腺癌,。這兩個基因分別是雌激素受體α和p53,，科學(xué)家們認(rèn)為健康婦女體內(nèi)的這兩個基因能夠成為生物標(biāo)志物，幫助預(yù)測未來的乳腺癌風(fēng)險，文章在5月15日發(fā)布的Cancer Research上,。
文章的通訊作者是喬治敦大學(xué)醫(yī)學(xué)中心的腫瘤學(xué)教授Priscilla A. Furth博士,，第一作者是Edgar S.Díaz-Cruz博士。Furth實驗室的重心是最終開發(fā)出一組檢測,，以便準(zhǔn)確判定婦女在未來患上乳腺癌的風(fēng)險,。為了發(fā)現(xiàn)這些攜帶風(fēng)險的基因和蛋白，她開發(fā)出獨特的小鼠模型,，在其中操作各種遺傳因子,，以便了解乳腺癌風(fēng)險如何隨時間改變。
Furth博士表示：“人們認(rèn)為,，這兩個基因只在乳腺癌形成之后才起作用,。p53在多種癌癥中發(fā)現(xiàn)，包括乳腺癌,，而大部分患有乳腺癌的婦女都有著雌激素受體過表達(dá),。人們不知道的是，這兩個基因的表達(dá)水平不同,，能引發(fā)細(xì)胞內(nèi)變化,，從而導(dǎo)致乳腺癌。”
在這項研究中,，Díaz-Cruz和Furth開發(fā)出一個p53基因拷貝沉默的小鼠,，并檢測它對腫瘤形成的影響。眾所周知,，p53基因是非常強(qiáng)大的腫瘤抑制劑,。在30-40%的人乳腺癌中報道有p53的改變，而這種沉默也與癌癥侵襲性增加,、預(yù)后差和化療耐藥性有關(guān),。
研究人員還將雌激素受體的表達(dá)調(diào)高了2倍。大約70%患有乳腺癌的婦女都呈雌激素受體陽性,，意味著雌激素受體推動了細(xì)胞生長,，因為它與乳腺細(xì)胞外部過量的受體結(jié)合。
這兩種小鼠模型都在乳腺組織中表現(xiàn)出明顯的癌前改變,。他們隨后比較了一個p53基因和兩倍雌激素受體表達(dá)的變化,，發(fā)現(xiàn)了其早期乳腺癌發(fā)展的跡象更明顯。
Furth認(rèn)為：“正常的乳腺組織功能需要細(xì)胞增長和細(xì)胞死亡的平衡,，在這項研究中,，我們發(fā)現(xiàn)了失調(diào)的雌激素受體和p53表達(dá)獨立且共同改變了這種平衡，并改變細(xì)胞,。”Furth認(rèn)為負(fù)責(zé)乳腺癌發(fā)展的分子可不止這兩種,，但是它們比較重要,，能提供早期警告甚至是預(yù)防策略。(生物谷Bioon.com)
生物谷推薦原文出處：
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.
