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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德克薩斯州大學(xué)西南醫(yī)學(xué)中心的研究人員首次描述了一個基因的多個拷貝如何導(dǎo)致早期階段乳腺癌的轉(zhuǎn)移和病患者差的預(yù)后,?？窃谏现艿摹睹绹茖W(xué)院院刊》雜志上的一項研究中,，一種叫做uPAR的基因為中止或緩解乳腺癌惡化的藥物提供了一個有潛力的靶標(biāo),，并且該基因可能成為評估患者個體對藥物的應(yīng)答的篩選工具,。
這種基因啟動了一種生化過程,，在這個過程中，一種叫做血漿酶（plasmin）的分子能夠在組織膜上打孔,，并導(dǎo)致膜降解,，從而使癌細(xì)胞能夠流竄到血管和臨近組織。這種過程的結(jié)果就是導(dǎo)致轉(zhuǎn)移性乳腺癌,。已經(jīng)知道,，大約20％到25％的乳腺癌患者出現(xiàn)了uPAR基因的擴增，即他們攜帶這種基因的很多拷貝,。
研究人員推測,，uPAR可能放大HER-2的致癌作用。這種由uPAR觸發(fā)的生化過程叫做尿激酶血漿酶原活化因子系統(tǒng),，是其中一個乳腺癌預(yù)后因子,。
此前，幾乎所有的研究都集中在蛋白質(zhì)和酶活性上,，而不是這種基因的擴增,，這種診斷方法稱為FISH。另外一個重要的發(fā)現(xiàn)是HER-2和uPAR基因擴增往往共存,，并且這對新的治療策略具有重要意義,。這項新的研究為增加藥物Herceptin的療效開啟了一個有潛力的新途徑，即通過增加第二種藥物還沉默uPAR基因,，進而提高Herceptin效果,。
Uhr博士表示，進化乳腺癌藥物研究的一個重要的方向?qū)⒖赡苁情_發(fā)一種能夠阻止uPAR與能活化uPAR的uPA分子結(jié)合的抗體,。
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.
