Roll of Nitrous Oxide (NO) and Cyclic GMP in Cancer

这个项目主要关注乳腺癌转移和复发的问题，以及一种新的信号转导机制 定位为调节两者的通路。关键的信号分子是可溶性鸟酸盐的β1亚单位 环酶(SGC)，一种通常作为由α1和β1亚基组成的杂二聚体的酶 这里sgcα1和sgcβ1)。在生物模型中，sGCβ1，而不是sGCα1，可以移位到细胞核，在那里 它调节P53和特定的细胞周期蛋白依赖蛋白激酶的表达，并诱导G0/G1期停滞。 此外，sGCβ1，而不是sGCα1，显著抑制人癌细胞的增殖和集落形成， 与对照组相比，显著延长了正交异性移植小鼠的存活时间。在人类乳腺癌患者中，水平 在16 6 4例乳腺癌患者中，sGCβ1(而不是sGCα1)的表达与患者的生存直接相关。 SGCβ1在肿瘤间质(包括上皮细胞、免疫细胞和 血管内皮细胞)改变对利基信号的反应，并调节乳腺癌的复发 通过(1)询问sGCβ-1表达对循环肿瘤细胞簇集形成的影响来检验，(2) 检测sGCβ1表达在调控乳腺癌血管生成复发中的作用 休眠，以及(3)确定sGCβ1靶向组蛋白脱乙酰酶信号逆转免疫的能力 功能障碍。成功完成后，该项目将验证SGCHDAC 1目标β信令的重要性 防止潜伏期乳腺癌的复发，并为治疗指明新的治疗策略 转移性乳腺癌。

This project focuses on the problem of breast cancer metastasis and recurrence, and on a novel signaling pathway that is positioned to modulate both. The key signaling molecule is the β1 subunit of soluble guanylate cyclase (sGC), an enzyme that normally functions as a heterodimer composed of α1 and β1 subunits (termed here sGCα1 and sGCβ1). In biological models, sGCβ1, but not sGCα1, can translocate into the nucleus, where it regulates expression of p53 and specific cyclin dependent protein kinases and induces G0/G1 phase arrest. Moreover sGCβ1, but not sGCα1, markedly inhibits proliferation and colony formation of human cancer cell lines, and lengthens survival time of orthotropic implanted mice over control. In human breast cancer patients, levels of sGCβ1 (but not sGCα1) directly correlate with patient survival in authentic breast cancer patients (n =1664). The hypothesis that altered expression of sGCβ1 in tumor stroma (including epithelial cells, immune cells, and vascular endothelial cells) alters responses to niche signals and modulates breast cancer recurrence will be tested by (1) interrogating the effects of sGCβ1 expression on circulating tumor cell (CTC) cluster formation, (2) examining the role of sGCβ1 expression in modulating breast cancer recurrence arising from angiogenic dormancy, and (3) determining the ability of sGCβ1-targeted histone deacetylase signaling to reverse immune dysfunction. Successfully completed, this project will validate the importance of sGCβ1-targeted HDAC signaling against recurrence of dormant breast cancer, and point the field toward new therapeutic strategies for treating metastatic breast cancer.