Prueitt Robyn L, Boersma Brenda J, Howe Tiffany M, Goodman Julie E, Thomas Douglas D, Ying Lei, Pfiester Candice M, Yfantis Harris G, Cottrell John R, Lee Dong H, Remaley Alan T, Hofseth Lorne J, Wink David A, Ambs Stefan
Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
Int J Cancer. 2007 Feb 15;120(4):796-805. doi: 10.1002/ijc.22336.
Akt signaling may promote breast cancer progression and poor disease outcome. We hypothesized that serum insulin-like growth factor I (IGF-I) and a proinflammatory tumor environment induce phosphorylation of Akt and downstream targets of Akt in breast cancer. We studied the relationship between Akt pathway activation, IGF-I and markers of inflammation, e.g., nitric oxide synthase-2 (NOS2), cyclooxygenase-2 (COX2) and tumor phagocyte density, in 248 breast tumors. We also examined the association of Akt phosphorylation with breast cancer survival. We observed that phosphorylation of Akt, BAD and caspase-9 correlated strongly with the expression of the 2 proinflammatory enzymes, NOS2 and COX2, in breast tumors (p < 0.001; Spearman rank correlation). Both NOS2 and COX2 expression were independently associated with Akt phosphorylation in the multivariate analysis. Serum IGF-I concentrations and the IGF-I/IGFBP3 ratio correlated with Akt phosphorylation at Thr308 and Ser473 in breast tumors (p <or= 0.05; Spearman rank correlation). The association with Akt phosphorylation at Thr308 remained statistically significant in the multivariate analysis. Akt pathway activation was not associated with overall survival in the unstratified analysis, but we observed a statistical interaction between Akt phosphorylation and tumor phagocyte density on breast cancer survival (p(interaction) < 0.05). We further corroborated our findings in cell culture models by demonstrating that ANA-1 macrophages, nitric oxide and prostaglandin E(2) induce Akt phosphorylation in human breast cancer cells. In summary, a proinflammatory environment was found to activate the Akt pathway in breast cancer, and may modify the association between the Akt phosphorylation status and breast cancer survival.
Akt信号传导可能促进乳腺癌进展及不良疾病预后。我们推测血清胰岛素样生长因子I（IGF-I）和促炎性肿瘤环境可诱导乳腺癌中Akt及其下游靶点的磷酸化。我们研究了248例乳腺肿瘤中Akt通路激活、IGF-I与炎症标志物（如一氧化氮合酶-2（NOS2）、环氧化酶-2（COX2））及肿瘤吞噬细胞密度之间的关系。我们还检测了Akt磷酸化与乳腺癌生存的相关性。我们观察到，乳腺肿瘤中Akt、BAD和caspase-9的磷酸化与两种促炎酶NOS2和COX2的表达密切相关（p < 0.001；Spearman等级相关性）。在多变量分析中，NOS2和COX2的表达均与Akt磷酸化独立相关。血清IGF-I浓度及IGF-I/IGFBP3比值与乳腺肿瘤中Thr308和Ser473位点的Akt磷酸化相关（p≤0.05；Spearman等级相关性）。在多变量分析中，与Thr308位点Akt磷酸化的相关性仍具有统计学意义。在未分层分析中，Akt通路激活与总生存期无关，但我们观察到Akt磷酸化与肿瘤吞噬细胞密度在乳腺癌生存方面存在统计学交互作用（p(交互作用) < 0.05）。我们通过证明ANA-1巨噬细胞、一氧化氮和前列腺素E2可诱导人乳腺癌细胞中Akt磷酸化，在细胞培养模型中进一步证实了我们的发现。总之，发现促炎性环境可激活乳腺癌中的Akt通路，并可能改变Akt磷酸化状态与乳腺癌生存之间的关联。
