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: 8937667
• 负责人: DAVID SALOMON
• 金额: $ 125.58万
• 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/8937667
• 关键词: 1-Phosphatidylinositol 3-Kinase; Activins; Antibodies; Binding; Biological Process; Breast Cancer Cell; Breast Epithelial Cells; CFC1 gene; Cancer cell line; Carcinoma; Cell surface; Chordata; Colon Carcinoma; Dimerization; EGF gene; Embryo; Epithelial; 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; human NR5A2 protein; 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.

我们的实验室研究了EGF-CFC家族及其在小鼠乳腺发育以及小鼠和人乳腺癌发生和发展中的作用。EGF-CFC家族已在所有脊索动物物种中得到鉴定，由Cripto-1（CR-1）和Cryptic组成，它们作为TGF β蛋白亚家族Nodal/GDF 1/GDF 3的共受体发挥强制性作用，并调节原肠胚形成、种系层形成和左右轴确定。此外，Nodal和Cripto-1在维持胚胎干细胞（ES）的自我更新和多能性方面至关重要。Nodal与cripto-1的结合通过ALK 4和Act-R-IIB激活素/TGF β类丝氨酸-苏氨酸激酶受体发挥作用，以通过与Smad 4的二聚化激活典型的Smad 2和Smad 3细胞内信号传导途径。我们已经表明，人CR-1在大约40-90%的各种人类癌包括乳腺肿瘤中过表达。我们还发现，Cr-1或CR-1在小鼠乳腺上皮细胞中作为转基因在体外和体内的过表达导致它们的转化以及它们作为上皮-间充质转化（EMT）的结果而增强的迁移和侵袭能力。我们能够证明CR-1还可以通过结合磷脂酰肌醇蛋白聚糖-1并通过随后激活c-src、MAPK、PI-3激酶和Akt来激活Nodal和ALK 4非依赖性信号传导途径，这些对于CR-1刺激EMT至关重要。我们最近还发现，Cripto-1可以通过促进Wnt与细胞表面上的Lrp 5或Lrp 6共受体的结合，在有限浓度的Wnt下增强经典Wnt/β-连环蛋白信号传导。最后，我们发现两个转录因子，LRH-1和GCNF，可以积极和消极地调节CR-1的表达，分别在人乳腺癌细胞系。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，并且与更分化的管腔A和管腔B乳腺肿瘤相比，LRH-1和CR-1表达的这种相关性在HER+和三阴性乳腺肿瘤（HER-、ER-和PR-）中更频繁地发生。