科学家分析了与乳腺癌有关联的基因的统计数据,结果发现了一个特效的分子靶标——这是已知的第二个分子靶标。它有可能对药物治疗做出响应。出现乳腺癌是因为多种突变或基因表达水平的变化。某些肿瘤过度表达ERBB2受体;医生已经成功使用了一种称为曲妥珠单抗的单克隆抗体阻止了这种受体在乳腺癌患者体内的活动。
Arul Chinnaiyan及其同事进行了一场元研究,从而分析了乳腺癌的基因过度表达,结果发现,除了ERBB2,AGTR1受体在一些肿瘤中也有类似的过度表达。这组作者使用了此前开发的一种方法发现了其他研究获得的31个乳腺癌谱数据中的过度表达的基因。ERBB2 在这项元研究中的得分最高;与癌症有关的AGTR1是得分第二高的基因。这组作者还进行了细胞和动物移植研究,从而检查了AGTR1过度表达的效应,结果证明了这种受体看上去并不影响肿瘤增殖,而是增加癌细胞的入侵行为。一种常用药氯沙坦已知可以抑制AGTR1。(生物谷Bioon.com)
生物谷推荐原始出处:
PNAS June 1, 2009, doi: 10.1073/pnas.0900351106
AGTR1 overexpression defines a subset of breast cancer and confers sensitivity to losartan, an AGTR1 antagonist
Daniel R. Rhodesa,b,1, Bushra Ateeqa,b,1, Qi Caoa,b,1, Scott A. Tomlinsa,b,1, Rohit Mehraa,b, Bharathi Laxmana,b, Shanker Kalyana-Sundarama,b, Robert J. Lonigroa,c, Beth E. Helgesona,b, Mahaveer S. Bhojanic,d, Alnawaz Rehemtullac,d, Celina G. Kleerb,c, Daniel F. Hayesc,e, Peter C. Lucasb,c, Sooryanarayana Varamballya,b,c and Arul M. Chinnaiyana,b,c,f,g,2
Breast cancer patients have benefited from the use of targeted therapies directed at specific molecular alterations. To identify additional opportunities for targeted therapy, we searched for genes with marked overexpression in subsets of tumors across a panel of breast cancer profiling studies comprising 3,200 microarray experiments. In addition to prioritizing ERBB2, we found AGTR1, the angiotensin II receptor type I, to be markedly overexpressed in 10–20% of breast cancer cases across multiple independent patient cohorts. Validation experiments confirmed that AGTR1 is highly overexpressed, in several cases more than 100-fold. AGTR1 overexpression was restricted to estrogen receptor-positive tumors and was mutually exclusive with ERBB2 overexpression across all samples. Ectopic overexpression of AGTR1 in primary mammary epithelial cells, combined with angiotensin II stimulation, led to a highly invasive phenotype that was attenuated by the AGTR1 antagonist losartan. Similarly, losartan reduced tumor growth by 30% in AGTR1-positive breast cancer xenografts. Taken together, these observations indicate that marked AGTR1 overexpression defines a subpopulation of ER-positive, ERBB2-negative breast cancer that may benefit from targeted therapy with AGTR1 antagonists, such as losartan.