Nat Commun：蛋白TGF-β提高乳腺癌干细胞数量

表达低水平紧密连接蛋白(claudin)的乳腺瘤在所有乳腺瘤中所占比例高达10%。在这类乳腺瘤中，来自英国癌症研究中心(Cancer Research UK)的研究人员发现一种关键性蛋白如何通过提高肿瘤内癌干细胞的数量，来促进乳腺癌生长。相关研究近期刊登在Nature Communications期刊上。

在今年早期，研究人员已发现乳腺癌其实是多种独特的疾病的一种泛称，并根据与乳腺癌病人存活相关的常见遗传特征而将它分为10种亚型(参见新闻：英研究确认10个乳腺癌疾病亚型)。

在这项研究中，研究人员利用这种知识首次研究了转化生长因子β(Transforming Growth Factor Beta, TGF-β)激活的基因网络在不同类型的乳腺癌之间如何存在差异。他们揭示，在表达低水平紧密连接蛋白的乳腺癌中，TGF-β激活一种特异性的提高乳腺癌干细胞数量的基因网络。乳腺癌干细胞促进乳腺癌扩散，并且与病人较差的存活率相关联。

在蛋白NEDD9的作用下，TGF-β调节两个其他的蛋白Smad和SRF来发挥作用，而这有助于这三个蛋白组装成有活性的复合体。

论文通信作者Alejandra Bruna博士说，“多年来，科学家们一直对TGF-β如何能够促进和抑制乳腺癌生长感到迷惑。如今，多亏我们对不同遗传类型的乳腺癌的深入理解，我们就能够精确地找到一种特异性通路来解释这些差异。”

doi: 10.1038/ncomms2039
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TGFβ induces the formation of tumour-initiating cells in claudin^low breast cancer

Alejandra Bruna, Wendy Greenwood, John Le Quesne, Andrew Teschendorff, Diego Miranda-Saavedra, Oscar M. Rueda, Jose L. Sandoval, Ana Tufegdzic Vidakovic, Amel Saadi, Paul Pharoah, John Stingl & Carlos Caldas

The role of transforming growth factor-beta (TGFβ) in the progression of different molecular subtypes of breast cancer has not been clarified. Here we show that TGFβ increases breast tumour-initiating cell (BTIC) numbers but only in claudinlow breast cancer cell lines by orchestrating a specific gene signature enriched in stem cell processes that predicts worse clinical outcome in breast cancer patients. NEDD9, a member of the Cas family of integrin scaffold proteins, is necessary to mediate these TGFβ-specific effects through a positive feedback loop that integrates TGFβ/Smad and Rho-actin-SRF-dependent signals. In normal human mammary epithelium, TGFβ induces progenitor activity only in the basal/stem cell compartment, where claudinlow cancers are presumed to arise. These data show opposing responses to TGFβ in both breast malignant cell subtypes and normal mammary epithelial cell subpopulations and suggest therapeutic strategies for a subset of human breast cancers.