Glycolytic signaling of p38gamma in breast cancer

三阴性乳腺癌不表达雌激素受体（ER）、孕激素受体（PR） 和Her 2作为治疗靶点，因此在所有类型的乳腺癌中具有最差的预后。 代谢重编程向有氧糖酵解（也称为瓦尔堡效应）是癌症的标志， 其在TNBC中被进一步激活。尽管有氧糖酵解可能是治疗靶向的，但可药用的糖酵解可能是治疗靶向的。 路径尚未确定。p38 β是TNBC致癌基因，刺激葡萄糖摄取和代谢 适应该提议将检验p38 β通过刺激TNBC的表达而促进TNBC肿瘤发生的假设。 PFKFB 3/GLUT 1依赖性有氧糖酵解。 这一假说基于以下发现：1）p38 β刺激葡萄糖转运蛋白1（GLUT 1） 表达并增加葡萄糖摄取; 2）p38 β促进TNBC肿瘤发生; 3）TNBC高度表达， 糖酵解与PFKFB 3和GLUT 1表达升高; 4）p38 β结合PFKFB 3，一种关键的糖酵解激活剂， 在TNBC细胞中，它与糖酵解三个家族成员（PFKFB 1、2和4）的相互作用要少得多。 TNBC细胞; 5）MS/MS分析鉴定p38在S467处使PFKFB 3磷酸化，导致其稳定化， 而公共数据库的数据显示，在侵袭性乳腺癌中，p38 β基因表达与GLUT 1相关， 乳腺癌组织; 6）条件性p38敲除（KO）抑制TNBC样PyMT小鼠中的肿瘤发生 遗传性乳腺癌模型并降低PFKFB 3/GLUT 1表达; 7）TNBC中p38过表达 细胞增加PFKFB 3/GLUT 1丰度，促进它们的相互作用，并刺激ECAR（ 糖酵解），表明其通过形成三元复合物刺激有氧糖酵解的活性;和8） 药理学p38 β 1和PFKFB 3抑制剂协同降低p-PFKFB 3/PFKFB 3/GLUT 1水平， 以依赖于p38 β的方式抑制TNBC生长。这些结果共同表明，p38与 有氧糖酵解和TNBC肿瘤发生通过激活PFKFB 3和GLUT 1。 我们将通过以下目标来检验这一假设：AIM 1将研究p38是否与有氧代谢相关。 通过与PFKFB 3相互作用和刺激PFKFB 3的糖酵解和TNBC肿瘤发生 AIM 2将决定p38 β是否与PFKFB 3和GLUT 1共同作用， 有氧糖酵解和TNBC肿瘤发生通过刺激S467依赖性三元复合物;和AIM 3将 确定p38 β-PFKFB 3激酶级联是否是TNBC的治疗靶点，以及p38 β-PFKFB 3/Glu 1是否是TNBC的治疗靶点。 与升高的p-PFKFB 3的共上调鉴定了临床上预后更差的TNBC亚组。这些 研究将证明p38 β-PFKFB 3激酶级联是否是TNBC的新治疗靶点，并揭示 如果联合应用p38 κ B/PFKFB 3药理学抑制剂是一种潜在的有效治疗方法， 这将影响TNBC临床结果和退伍军人医疗保健的战略。

Triple-negative breast cancer (TNBC) does not express estrogen receptor (ER), progesterone receptor (PR) and Her2 as therapeutic targets and consequently has the worst prognosis among all types of breast cancers. Metabolic reprogramming toward aerobic glycolysis (also called the Warburg effect) is a hallmark of cancer, which is further activated in TNBC. Although aerobic glycolysis may be therapeutically targeted, the druggable pathway has not been identified. p38 is a TNBC oncogene and stimulates glucose uptake and metabolic adaption. This proposal will test the hypothesis that p38 promotes TNBC oncogenesis by stimulating PFKFB3/GLUT1-dependent aerobic glycolysis. This hypothesis is based on the following findings: 1) p38 stimulates glucose transporter 1 (GLUT1) expression and increases glucose uptake; 2) p38 promotes TNBC oncogenesis; 3) TNBCs are highly glycolytic with elevated PFKFB3 and GLUT1 expression; 4) p38 binds PFKFB3, a key glycolytic activator, in TNBC cells, whereas it interacts with much less glycolytic three family members (PFKFB1, 2 and 4) in non- TNBC cells; 5) MS/MS analysis identifies that p38 phosphorylates PFKFB3 at S467 leading to its stabilization, whereas data from public data-base shows that p38 gene expression is correlated with GLUT1 in invasive breast cancer tissues; 6) conditional p38 knockout (KO) inhibits tumorigenesis in a TNBC-like PyMT mouse genetic breast cancer model and decreases PFKFB3/GLUT1 expression; 7) p38 overexpression in TNBC cells increases PFKFB3/GLUT1 abundance, promotes their interaction, and stimulates ECAR (an indicator of glycolysis), indicating its activity of stimulating aerobic glycolysis by forming a ternary complex; and 8) pharmacological p38 and PFKFB3 inhibitors cooperatively decrease p-PFKFB3/PFKFB3/GLUT1 levels and inhibit TNBC growth in a manner dependent on p38. These results together indicate that p38 links aerobic glycolysis and TNBC oncogenesis through activating PFKFB3 and GLUT1. We will test this hypothesis by targeting the following aims: AIM 1 will investigate if p38 links aerobic glycolysis and TNBC oncogenesis through interaction with PFKFB3 and stimulating of PFKFB3 phosphorylation at S467; AIM 2 will determine if p38 cooperates with both PFKFB3 and GLUT1 to promote aerobic glycolysis and TNBC oncogenesis by stimulating a S467-dependent ternary-complex; and AIM 3 will determine if the p38-PFKFB3 kinase cascade is a therapeutic target for TNBC and if the p38/PFKFB3/Glut1 co-upregulation with elevated p-PFKFB3 identifies a subgroup of TNBC with a worse prognosis in clinic. These studies will demonstrate if the p38-PFKFB3 kinase cascade is a novel therapeutic target for TNBC and reveal if a combined application of p38/PFKFB3 pharmacological inhibitors is a potential effective therapeutic strategy that will impact TNBC clinical outcome and veteran health care.