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

该项目的重点是乳腺癌转移和复发的问题，并在一个新的信号 这两种信号通路都被定位来调节。关键的信号分子是可溶性鸟苷酸β1亚基 环化酶（sGC），一种通常作为由α1和β1亚基组成的异二聚体发挥功能的酶（称为 此处为sGCα1和sGCβ1）。在生物模型中，sGCβ1（而不是sGCα1）可以易位到细胞核中， 它调节p53和特异性细胞周期蛋白依赖性蛋白激酶的表达并诱导G 0/G1期阻滞。 此外，sGCβ1而不是sGCα1显著抑制人癌细胞系的增殖和集落形成， 并延长正交植入小鼠的存活时间。在人类乳腺癌患者中， sGCβ1（而不是sGCα1）的水平与真实乳腺癌患者的生存率直接相关（n =1664）。 假设sGCβ1在肿瘤间质（包括上皮细胞、免疫细胞和肿瘤细胞）中的表达改变， 血管内皮细胞）改变对小生境信号的反应并调节乳腺癌复发将是 通过（1）询问sGCβ1表达对循环肿瘤细胞（CTC）簇形成的影响，（2） 研究sGCβ1表达在调节血管生成性乳腺癌复发中的作用， 休眠，和（3）确定sGCβ1靶向的组蛋白脱乙酰酶信号转导逆转免疫的能力 功能障碍成功完成后，该项目将验证sGCβ1靶向HDAC信号传导的重要性 针对休眠乳腺癌的复发，并指出该领域的新的治疗策略， 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.