Radiation Biology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Trends Pharmacol Sci. 2011 Nov;32(11):644-51. doi: 10.1016/j.tips.2011.07.001. Epub 2011 Sep 4.
Basal-like breast cancer is an aggressive disease with limited therapeutic options because these tumors frequently express the 'triple-negative' phenotype. We have recently reported that inducible nitric oxide synthase (NOS2) is a strong predictor of survival in patients with estrogen receptor negative [ER(-)] breast cancer, and that NOS2 expression is correlated with a basal-like phenotype. Recent reports also describe the pro-tumor effects of NO in breast and many other types of cancer. NO promotes cancer progression by activating several oncogenic signaling pathways such as extracellular signal-regulated kinases (ERK)-1/2, phosphoinositide 3-kinases (PI3K)/Akt, and c-Myc. Protein phosphatase 2A (PP2A) is a tumor suppressor that negatively regulates the same cancer-related signaling pathways that are activated by NO. PP2A activity is suppressed in tumor cells, but potential pharmacological agents have recently been described to increase PP2A activity in ER(-) breast cancer cells. We examine here the various functions of NO and PP2A in breast cancer and propose a novel mechanism by which activation of PP2A antagonizes NO signaling that promotes ER(-) breast cancer.
基底样乳腺癌是一种侵袭性疾病，治疗选择有限，因为这些肿瘤经常表达“三阴性”表型。我们最近报道，诱导型一氧化氮合酶（NOS2）是雌激素受体阴性[ER（-）]乳腺癌患者生存的强有力预测因子，并且 NOS2 表达与基底样表型相关。最近的报告还描述了 NO 在乳腺和许多其他类型癌症中的促肿瘤作用。NO 通过激活细胞外信号调节激酶（ERK）-1/2、磷酸肌醇 3-激酶（PI3K）/Akt 和 c-Myc 等几种致癌信号通路促进癌症进展。蛋白磷酸酶 2A（PP2A）是一种肿瘤抑制因子，可负调控被 NO 激活的与癌症相关的信号通路。PP2A 活性在肿瘤细胞中受到抑制，但最近描述了潜在的药理学药物可增加 ER（-）乳腺癌细胞中的 PP2A 活性。我们在此研究了 NO 和 PP2A 在乳腺癌中的各种功能，并提出了一种新的机制，即激活 PP2A 拮抗促进 ER（-）乳腺癌的 NO 信号。
