Researchers including Drs. Jonathan Uhr (left) and Debu Tripathy have for the first time described how copies of a gene are responsible for metastases in early-stage breast cancer. The gene, called uPAR,...
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德克萨斯州大学西南医学中心的研究人员首次描述了一个基因的多个拷贝如何导致早期阶段乳腺癌的转移和病患者差的预后。刊登在上周的《美国科学院院刊》杂志上的一项研究中，一种叫做uPAR的基因为中止或缓解乳腺癌恶化的药物提供了一个有潜力的靶标，并且该基因可能成为评估患者个体对药物的应答的筛选工具。
这种基因启动了一种生化过程，在这个过程中，一种叫做血浆酶（plasmin）的分子能够在组织膜上打孔，并导致膜降解，从而使癌细胞能够流窜到血管和临近组织。这种过程的结果就是导致转移性乳腺癌。已经知道，大约20％到25％的乳腺癌患者出现了uPAR基因的扩增，即他们携带这种基因的很多拷贝。
研究人员推测，uPAR可能放大HER-2的致癌作用。这种由uPAR触发的生化过程叫做尿激酶血浆酶原活化因子系统，是其中一个乳腺癌预后因子。
此前，几乎所有的研究都集中在蛋白质和酶活性上，而不是这种基因的扩增，这种诊断方法称为FISH。另外一个重要的发现是HER-2和uPAR基因扩增往往共存，并且这对新的治疗策略具有重要意义。这项新的研究为增加药物Herceptin的疗效开启了一个有潜力的新途径，即通过增加第二种药物还沉默uPAR基因，进而提高Herceptin效果。
Uhr博士表示，进化乳腺癌药物研究的一个重要的方向将可能是开发一种能够阻止uPAR与能活化uPAR的uPA分子结合的抗体。
英文原文：
Analysis of breast-cancer gene role offers promising target
Researchers at UT Southwestern Medical Center have for the first time described how multiple copies of a gene are responsible for metastases in early-stage breast cancer and poor prognosis for patients.
In a study published in this week's issue of the Proceedings of the National Academy of Sciences, the gene, called uPAR, offers a promising target for therapeutic drugs to stop or slow the progression of the disease and could serve as a screening tool for assessing which types of drugs a patient will respond to.
The gene launches a biochemical process in which a molecule called plasmin perforates the membranes of tissues, causing the membranes to break down and allowing the cancer cells to escape into the bloodstream and to adjacent tissues. The result is metastasizing breast cancer. About 20 percent to 25 percent of breast-cancer patients were shown to have uPAR gene amplification, which means they carry too many copies of the gene.
"The uPAR system probably plays a role in metastases in many of the common solid tumors," said Dr. Jonathan Uhr, professor in the Cancer Immunobiology Center and of microbiology and the study's senior author.
While analyzing slides of individual tumor cells ?either from the primary tumor or circulating tumor cells ?of 72 patients with advanced recurrent breast carcinoma, the UT Southwestern research team discovered how uPAR may work in concert with another known breast cancer gene, HER-2.
The researchers suggest that uPAR may amplify the cancer-causing effects of HER-2.
"This gene, uPAR, is an important oncogene, and that is why we determined whether or not it is amplified," said Dr. Uhr. "Unexpectedly, it is usually amplified in the same tumor cell with HER-2 gene amplification. This has significant implications for treatment with targeting agents. Moreover, we stress the value of individual tumor cell analysis for providing information that cannot be obtained by conventional pathological examination."
Dr. Debu Tripathy, professor of internal medicine, director of the Komen/UT Southwestern Breast Cancer Research Program and a coauthor of the study, said the biochemical process triggered by uPAR, called the urokinase plasminogen activator system, is one of the breast-cancer prognostic factors that has the greatest level of evidence.
"All the work has been on the protein and enzymatic activity and not amplification of the gene, which is a very reliable and easy-to-use diagnostic test called FISH," said Dr. Tripathy. "The other important finding is that HER-2 and uPAR gene amplification tend to co-exist, and this has implications in new strategies to address HER-2-positive breast cancer with drugs that block both HER-2 and urokinase given together."
The study opens a promising avenue to increase the effectiveness of the drug trastuzumab (Herceptin) by adding a second drug seeking to neutralize the uPAR gene.
"One major avenue of investigation would be to develop an antibody that prevents uPAR from binding to a molecule called uPA that can activate uPAR," Dr. Uhr said.
