美国研究人员发现了一种与乳腺癌有密切关系的基因，这种基因是造成70%的顽固性乳腺癌的“罪魁祸首”。新发现将帮助科研人员研发出更有效的药物治疗乳腺癌。
美国马萨诸塞州怀特黑德生物医学研究所的研究人员在本周的《自然》杂志上撰文说，他们利用一种新技术对基因进行测试，结果发现了这个名为“PHGDH”的基因。这种新技术是将具有破坏性的基因片段注入癌细胞中，以探明哪种基因与肿瘤的形成和生长有关。
他们发现，在对激素疗法具有抵抗力的顽固性乳腺癌细胞中，“PHGDH”基因的活跃程度超乎寻常，结果导致癌细胞的化学成分不停地发生变化，使激素疗法失去效果。
雌性激素可促进乳腺肿瘤生长，因此治疗乳腺癌也可以用抗雌激素等药物，这被称为激素疗法。但约有三分之一的乳腺癌病例是无法用激素类药物治疗的，又被称为顽固性乳腺癌。
研究人员指出，一旦确定“PHGDH”基因是导致顽固性乳腺癌的“元凶”，便可研发出专门破坏这种基因活动的药物。(生物谷 Bioon.com)
生物谷推荐原文出处：
Nature doi:10.1038/nature10350
Functional genomics reveal that the serine synthesis pathway is essential in breast cancer
Richard Possemato; Kevin M. Marks; Yoav D. Shaul; Michael E. Pacold; Dohoon Kim; Kvan Birsoy; Shalini Sethumadhavan; Hin-Koon Woo; Hyun G. Jang; Abhishek K. Jha; Walter W. Chen; Francesca G. Barrett; Nicolas Stransky; Zhi-Yang Tsun; Glenn S. Cowley; Jordi Barretina; Nada Y. Kalaany; Peggy P. Hsu; Kathleen Ottina; Albert M. Chan; Bingbing Yuan; Levi A. Garraway; David E. Root; Mari Mino-Kenudson; Elena F. Brachtel; Edward M. Driggers; David M. Sabatini
Cancer cells adapt their metabolic processes to drive macromolecular biosynthesis for rapid cell growth and proliferation1, 2. RNA interference (RNAi)-based loss-of-function screening has proven powerful for the identification of new and interesting cancer targets, and recent studies have used this technology in vivo to identify novel tumour suppressor genes3. Here we developed a method for identifying novel cancer targets via negative-selection RNAi screening using a human breast cancer xenograft model at an orthotopic site in the mouse. Using this method, we screened a set of metabolic genes associated with aggressive breast cancer and stemness to identify those required for in vivo tumorigenesis. Among the genes identified, phosphoglycerate dehydrogenase (PHGDH) is in a genomic region of recurrent copy number gain in breast cancer and PHGDH protein levels are elevated in 70% of oestrogen receptor (ER)-negative breast cancers. PHGDH catalyses the first step in the serine biosynthesis pathway, and breast cancer cells with high PHGDH expression have increased serine synthesis flux. Suppression of PHGDH in cell lines with elevated PHGDH expression, but not in those without, causes a strong decrease in cell proliferation and a reduction in serine synthesis. We find that PHGDH suppression does not affect intracellular serine levels, but causes a drop in the levels of α-ketoglutarate, another output of the pathway and a tricarboxylic acid (TCA) cycle intermediate. In cells with high PHGDH expression, the serine synthesis pathway contributes approximately 50% of the total anaplerotic flux of glutamine into the TCA cycle. These results reveal that certain breast cancers are dependent upon increased serine pathway flux caused by PHGDH overexpression and demonstrate the utility of in vivo negative-selection RNAi screens for finding potential anticancer targets.
