基于PDB文件1e9t利用PyMQL構(gòu)建TFF3蛋白結(jié)構(gòu)圖,，圖片來自維基共享資源。
三葉因子3(trefoil factor 3, TFF3)蛋白在正常乳腺中保護(hù)和維持上皮組織表面的完整性,。一項(xiàng)新研究發(fā)現(xiàn)盡管TFF3蛋白在分化很好的低度腫瘤中較高表達(dá),，但是它在乳腺癌浸潤(rùn)和轉(zhuǎn)移中發(fā)揮著一種更加險(xiǎn)惡的作用。這些研究結(jié)果在線發(fā)表在2012年3月那期The American Journal of Pathology期刊上,。
英國(guó)紐卡斯?fàn)柎髮W(xué)病理學(xué)系研究人員Felicity E.B. May教授說,，“我們的研究發(fā)現(xiàn)提示著TFF3被雌激素所調(diào)節(jié)和在乳腺上皮組織中發(fā)揮著有益作用。我們提出在乳腺癌變?cè)缙?，TFF3與乳腺上皮細(xì)胞的正常功能保持關(guān)聯(lián),。隨后，隨著腫瘤細(xì)胞分化能力丟失,，TFF3的功能改為促進(jìn)腫瘤發(fā)展,、浸潤(rùn)和淋巴結(jié)轉(zhuǎn)移。”
為了確定TFF3在乳腺癌中的作用,，研究人員測(cè)量了來自正常乳腺,、良性乳腺病灶、原位乳腺癌,、浸潤(rùn)性乳腺癌和受累淋巴結(jié)的組織樣品中TFF3的水平,。TFF3在研究的大多數(shù)良性和惡性的乳腺病灶中都表達(dá)。分化很好的腫瘤類型表達(dá)更高水平的TFF3,。而且TFF3蛋白表達(dá)和微血管密度存在顯著的正向關(guān)聯(lián),，提示著它在乳腺腫瘤中促進(jìn)血管生成。
這項(xiàng)研究的一種顯著性發(fā)現(xiàn)是TFF3表達(dá)和浸潤(rùn)性乳腺癌中更具轉(zhuǎn)移性的表型之間關(guān)聯(lián)的緊密性和一致性,。TFF3在與腫瘤轉(zhuǎn)移相關(guān)聯(lián)的原發(fā)性腫瘤中更加高水平的表達(dá),，而且在從原發(fā)性腫瘤內(nèi)遷移出來的惡性癌細(xì)胞中更是高水平的表達(dá)。
這似乎表明浸潤(rùn)性癌癥內(nèi)TFF3的正常極性分泌過程存在一種開關(guān),，它允許浸潤(rùn)性癌癥表現(xiàn)出促進(jìn)浸潤(rùn)的效應(yīng),。
這項(xiàng)研究提示著TFF3可能是在乳腺癌中介導(dǎo)雌激素不同效應(yīng)的眾多基因之一。May教授注意到,，“不過,，對(duì)雌激素受體和TFF3而言，矛盾一直存在：它們促進(jìn)乳腺癌上皮組織的正常生理功能,，但是也參與癌癥擴(kuò)散,。”
重要的是，研究人員也評(píng)估了TFF3作為淋巴血管浸潤(rùn)和淋巴結(jié)轉(zhuǎn)移的生物標(biāo)記物的潛力,。他們發(fā)現(xiàn)相比于他們分析的其他標(biāo)記物,，TFF3有著更強(qiáng)的預(yù)測(cè)能力，包括腫瘤惡性程度,、發(fā)病年齡,、腫瘤大小和類型以及雌激素和黃體素(progesterone)受體水平。May博士作下結(jié)論,，“我們的研究加強(qiáng)了這種觀點(diǎn)：TFF3表達(dá)水平值得作為一種預(yù)后標(biāo)記物和一種治療反應(yīng)的預(yù)測(cè)性標(biāo)記物進(jìn)行評(píng)價(jià),。它的惡性作用將可能在患有激素反應(yīng)性癌癥(hormone-responsive cancer)的女性中通過輔助性內(nèi)分泌治療得以減輕,。然而，利用TFF3作為一種激素反應(yīng)性的標(biāo)記物還需要進(jìn)行評(píng)估,。” (生物谷：towersimper編譯)
doi:10.1016/j.ajpath.2011.11.022
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TFF3 Is a Normal Breast Epithelial Protein and Is Associated with Differentiated Phenotype in Early Breast Cancer but Predisposes to Invasion and Metastasis in Advanced Disease
A.R.H. Ahmed, A.B. Griffiths, M.T. Tilby, B.R. Westley, and F.E.B. May
The trefoil protein TFF3 stimulates invasion and angiogenesis in vitro. To determine whether it has a role in breast tumor metastasis and angiogenesis, its levels were measured by immunohistochemistry in breast tissue with a specific monoclonal antibody raised against human TFF3. TFF3 is expressed in normal breast lobules and ducts, at higher levels in areas of fibrocystic change and papillomas, in all benign breast disease lesions, and in 89% of in situ and in 83% of invasive carcinomas. In well-differentiated tumor cells, TFF3 is concentrated at the luminal edge, whereas in poorly differentiated cells polarity is inverted and expression is directed toward the stroma. Expression was high in well-differentiated tumors and was associated significantly with low histological grade and with estrogen and progesterone receptor expression, accordant with induction of TFF3 mRNA by estrogen in breast cancer cells. Paradoxically, TFF3 expression was associated with muscle, neural, and lymphovascular invasion and the presence and number of involved lymph nodes, and it was an independent predictive marker of lymphovascular invasion and lymph node involvement. Consistent with an angiogenic function, TFF3 expression correlated strongly with microvessel density evaluated with CD31 and CD34. In conclusion, TFF3 is expressed in both the normal and diseased breast. Although associated with features of good prognosis, its profile of expression in invasive cancer is consistent with a role in breast tumor progression and tumor cell dissemination.
