The Role of Cripto in the Pathogenesis of Breast and Colon Cancer

我们的实验室研究了EGF-cfc家族及其在小鼠乳腺发育以及在小鼠和人类乳腺癌的发生和发展中的作用。EGF-cfc家族在所有脊索类物种中都已被发现，由CRIPTO-1(CR-1)和CRIPTIC组成，它们作为转化生长因子β亚家族蛋白Nodal/GDF1/GDF3的辅助受体，调节原肠形成、胚层形成和左右轴的确定。此外，Nodal和Cripto-1在维持胚胎干细胞(ES)自我更新和多能性方面也是必不可少的。结节通过ALK4和Act-R-IIB激活素/转化生长因子β类丝氨酸苏氨酸激酶受体与Cripto-1结合，通过与Smad4的二聚化激活典型的Smad2和Smad3细胞内信号通路。我们已经证明，人类CR-1在包括乳腺癌在内的各种人类癌症中约有40%-90%过表达。我们还发现，在体外和体内以转基因的形式在小鼠乳腺上皮细胞中过表达CR-1或CR-1会导致它们的转化，并由于上皮-间充质转化(EMT)而增强它们的迁移和侵袭能力。我们还证明了CR-1还可以通过与GLYPICAN-1结合以及随后激活c-src、MAPK、PI-3K和Akt等对CR-1刺激EMT至关重要的信号通路来激活Nodal和ALK4非依赖的信号通路。我们最近还发现，Cripto-1可以通过促进Wnt与细胞表面LRP5或LRP6辅助受体的结合，在Wnt的有限浓度下增强规范的Wnt/β-catenin信号。最后，我们发现两种转录因子，LRH-1和GCNF，可以分别正向和负向地调节人乳腺癌细胞系中CR-1的表达。在人类乳腺肿瘤的组织芯片中，发现CR-1的表达与LRH-1的表达相关，这种相关性在HER+和三阴性乳腺肿瘤(HER-、ER-和PR-)中更常见，与分化较高的腔A和腔B乳腺肿瘤相比。

Our laboratory studies the the EGF-CFC family and their role in the development of the mouse mammary gland and in the initiation and progression of mouse and human breast cancer. The EGF-CFC family has been identified in all chordate species and consists of Cripto-1 (CR-1) and Cryptic that perform an obligatory role as co-receptors for the TGF beta subfamily of proteins, Nodal/GDF1/GDF3 and that regulate gastrulation, germ layer formation and left-right axis determination. In addition, Nodal and Cripto-1 are essential in the maintenance of embryonic stem cell (ES) self renewal and pluripotency. Nodal binding to cripto-1 functions through the ALK4 and Act-R-IIB Activin/TGF beta class of serine-threonine kinase receptors to activate a canonical Smad2 and Smad3 intracellular signaling pathway through dimerization with Smad4. We have shown that human CR-1 is overexpressed in approximately 40-90% of a variety of human carcinomas including breast tumors. We have also found that overexpression of either Cr-1 or CR-1 in mouse mammary epithelial cells in vitro and in vivo as a transgene results in their transformation and in their enhanced ability to migrate and invade as a result of epithelial-mesenchymal transition (EMT). We were able to demonstrate that CR-1 can also activate Nodal and ALK4-independent signaling pathways by binding to glypican-1 and by subsequently activating c-src, MAPK, PI-3 kinase and Akt which are critical for CR-1 in stimulating EMT. We have also recently found that Cripto-1 can enhance canonical Wnt/beta-catenin signaling at limiting concentrations of Wnt by facilitating the binding of Wnt to the Lrp5 or Lrp6 co-receptors on the cell surface. Finally, we have found that two transcription factors, LRH-1 and GCNF, can positively and negatively regulate CR-1 expression, respectively, in human breast cancer cell lines. Expression of CR-1 was found to correlate with LRH-1 expression in a tissue microarray of human breast tumors and this correlation in LRH-1 and CR-1 expression occurs more frequently in HER+ and in triple negative breast tumors ( HER-, ER- and PR-) as compared to more differentiated Luminal A and Luminal B breast tumors.