Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720.
Proc Natl Acad Sci U S A. 2013 Oct 8;110(41):E3937-44. doi: 10.1073/pnas.1315022110. Epub 2013 Sep 25.
The protein 14-3-3σ (stratifin) is frequently described as a tumor suppressor silenced in about 80% of breast tumors. Intriguingly, we show that 14-3-3σ expression, which in normal breast is localized to the myoepithelial cells, tracks with malignant phenotype in two models of basal-like breast cancer progression, and in patients, it is associated with basal-like subtype and poor clinical outcome. We characterized a mechanism by which 14-3-3σ guides breast tumor invasion by integrating cytoskeletal dynamics: it stabilizes a complex of solubilized actin and intermediate filaments to maintain a pool of "bioavailable" complexes for polarized assembly during migration. We show that formation of the actin/cytokeratin/14-3-3σ complex and cellular migration are regulated by PKCζ-dependent phosphorylation, a finding that could form the basis for intervention in aggressive breast carcinomas expressing 14-3-3σ. Our data suggest that the biology of this protein is important in cellular movement and is contingent on breast cancer subtype.
蛋白质 14-3-3σ（层粘连蛋白）常被描述为一种肿瘤抑制因子，约 80%的乳腺癌中其表达沉默。有趣的是，我们发现 14-3-3σ在正常乳腺中的表达定位于肌上皮细胞，在两种基底样乳腺癌进展模型中与恶性表型相关，在患者中与基底样亚型和不良临床结局相关。我们通过整合细胞骨架动力学，描述了一种 14-3-3σ指导乳腺癌侵袭的机制：它稳定可溶性肌动蛋白和中间丝的复合物，以维持在迁移过程中进行极化组装的“可用”复合物池。我们表明，肌动蛋白/细胞角蛋白/14-3-3σ 复合物的形成和细胞迁移受 PKCζ依赖性磷酸化调节，这一发现可能为干预表达 14-3-3σ 的侵袭性乳腺癌提供基础。我们的数据表明，该蛋白的生物学特性在细胞运动中很重要，并且取决于乳腺癌亚型。
