阴阳：免疫信号蛋白在乳腺癌发生相反的作用
MD安德森新闻Release June 08, 2015
MD安德森研究表明TLR4在肿瘤生长的作用依赖于TP53突变
MD安德森新闻发布2015年6月8日
此前打击坚守的信念，研究人员在188bet体育网址得克萨斯大学MD安德森癌症中心的大学已经发现，抑制免疫受体蛋白TLR4可能不会在所有癌症明智的治疗策略。这是因为，TLR4可以促进或抑制乳腺癌细胞的生长依赖于一种称为TP53基因突变。
The TLR4 (Toll-like receptor 4) protein, like many other members of important immune system pathways, appears to be a promising target for immune-based therapeutic options and is the focus of many drugs currently in development. As TLR4 was previously thought to be an oncogene, or promoter of tumor growth, these drugs would aim to block its activity and kill cancer cells.
However, new research, published in theProceedings of the National Academy of Sciences报告说，TLR4的生长促进功能取决于TP53（肿瘤蛋白质p53），肿瘤生长的公知的抑制的活性。
“This study demonstrated that while TLR4 can function as an oncogene in some breast cancer cells, it acts as a growth suppressor in cases where TP53 is wild-type,” saysPowel Brown, M.D., Ph.D.，教授和椅子，临床癌症预防, and senior author. “Therefore, it may be dangerous to inhibit TLR4 in those cases as you may actually promote cancer growth.”
TLR4 was identified as a frequently mutated gene by MD Anderson’s Svasti Haricharan, Ph.D., Clinical Cancer Prevention, in a search for potential drivers of a particular subset of breast cancers with poor outcomes. However, Haricharan, lead author of the study, found that, contrary to expectations for an oncogene, expression of TLR4 was lower in breast cancers compared to normal tissue.
事实上，比较乳腺癌患者的生存时，哈理查伦发现更好的结果，用TLR4的高表达有关。这是一个致癌基因意外的结果，说明了布朗。
Haricharan then examined survival trends associated with TLR4 based on mutations in TP53, which is the most commonly mutated (>50%) gene across all cancer types. In cases with TP53 mutations, high levels of TLR4 were associated with low survival rates, as might be expected. Interestingly, in cases with wild-type, or normal, TP53, the trends were exactly the opposite.
所述TLR4蛋白通常在免疫细胞功能，以激活在对感染的反应的信号传导分子，但它可以以类似的方式起作用，以调节在癌细胞中的细胞生长。通过在乳腺癌细胞系操纵TLR4的活性，哈理查伦发现，通过生产的特定的野生型TP53癌细胞TLR4抑制生长信令化合物，干扰素γ。相反，在生产刺激生长的不同信号的TP53突变的细胞的结果TLR4活性。
重要的是，这项研究发现，TP53和TLR4之间的联系是不特定乳腺癌。与TP53的突变频率，如卵巢浆液性，头部和颈部，和膀胱癌恶性肿瘤，似乎都保持高TLR4水平。与TP53突变的癌症是更加积极和难以治疗，TLR4代表这些患者具有广泛有价值的目标。
“This looks like a promising avenue to develop drugs for the worst kinds of cancers,” says Brown. “However, if we wish to target this immune pathway, we better pay attention to the TP53 status of the tumor.”
TP53的作用已经被连接到阻力ce of some cancers to other therapies. Based on these results, the authors suggest the need for further exploration of the balance between the activity of drug targets and that of TP53.
Future work will focus on clarifying which mutations in TP53 are critical for the role of TLR4 in regulating cancer cell growth in order to better understand this complex interaction.
This study was funded by a Cancer Center Support Grant (5 P30 CA016672-38), a Norman Brinker Award for Research Excellence, a John Charles Cain Distinguished Chair Award, the Mariam Rogers Fund for Breast/Women’s Cancer Research, The University of Texas MD Anderson Cancer Center Halliburton Fellowship in Cancer Prevention Fund, and the Susan G. Komen Promise Grant (KG081694).