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

Cripto 在乳腺癌和结肠癌发病机制中的作用

• 批准号: 8552609
• 负责人: DAVID SALOMON
• 金额: $ 120.38万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8552609
• 关键词: 1-Phosphatidylinositol 3-Kinase; Activins; Antibodies; Binding; Biological Process; Breast Cancer Cell; CFC1 gene; Cancer cell line; Carcinoma; Cell surface; Chordata; Colon Carcinoma; Dimerization; EGF gene; Embryo; Epithelial; Epithelial Cells; Family; Genes; Germ Layers; Glypican; Human; In Vitro; Invaded; Laboratory Study; Left; MAP Kinase Gene; Maintenance; Malignant neoplasm of lung; Malignant neoplasm of pancreas; Mammary Neoplasms; Mammary gland; Mesenchymal; Mus; Nodal; Pathogenesis; Phase I Clinical Trials; Receptor Serine/Threonine Kinase; Regulation; Research; Role; SRC gene; Signal Pathway; Signal Transduction; Tissue Microarray; Toxin Conjugates; Transforming Growth Factor beta; Transforming Growth Factor beta Receptors; Transgenes; beta catenin; design; embryonic stem cell; gastrulation; in vivo; malignant breast neoplasm; malignant stomach neoplasm; mouse development; nodal protein; overexpression; pluripotency; programs; receptor; self-renewal; transcription factor

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.

我们的实验室研究EGF-CFC家族及其在小鼠乳腺发育和小鼠和人类乳腺癌的发生和进展中的作用。EGF-CFC家族已在所有脊椎动物中被鉴定出来，由Cripto-1 （CR-1）和Cryptic组成，它们作为TGF β亚家族蛋白Nodal/GDF1/GDF3的共受体发挥必要作用，并调节原肠形成、胚层形成和左右轴决定。此外，Nodal和Cripto-1在维持胚胎干细胞（ES）的自我更新和多能性中是必不可少的。通过ALK4和Act-R-IIB激活素/TGF β类丝氨酸-苏氨酸激酶受体与cripto-1的节点结合，通过与Smad4二聚化激活典型的Smad2和Smad3细胞内信号通路。我们已经证明，人类CR-1在大约40-90%的各种人类癌症中过度表达，包括乳腺肿瘤。我们还发现，在体外和体内的小鼠乳腺上皮细胞中，作为转基因的Cr-1或Cr-1过表达会导致其转化，并由于上皮-间质转化（EMT）而增强其迁移和侵袭能力。我们能够证明CR-1还可以通过结合glypican-1激活Nodal和alk4非依赖性信号通路，随后激活c-src、MAPK、PI-3激酶和Akt，这些对CR-1刺激EMT至关重要。我们最近还发现，通过促进Wnt与细胞表面的Lrp5或Lrp6共受体的结合，Cripto-1可以在限制Wnt浓度下增强典型Wnt/ β -连环蛋白信号传导。最后，我们发现两种转录因子LRH-1和GCNF在人乳腺癌细胞系中分别可以正向和负向调节CR-1的表达。在人乳腺肿瘤的组织微阵列中发现CR-1的表达与LRH-1的表达相关，与分化程度更高的乳腺肿瘤a和B相比，在HER+和三阴性乳腺肿瘤（HER-， ER-和PR-）中，LRH-1和CR-1表达的相关性更频繁。