COX-2 activation is associated with Akt phosphorylation and poor survival in ER-negative, HER2-positive breast cancer.
COX-2 activation is associated with Akt phosphorylation and poor survival in ER-negative, HER2-positive breast cancer.
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DOI：
10.1186/1471-2407-10-626
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发表时间：
2010-11-15
期刊：
影响因子：
3.8
通讯作者：
Ambs S
中科院分区：
文献类型：
--
作者：
Glynn SA;Prueitt RL;Ridnour LA;Boersma BJ;Dorsey TM;Wink DA;Goodman JE;Yfantis HG;Lee DH;Ambs S
诱导型环氧合酶-2 (COX-2) 通常在乳腺肿瘤中过度表达，是癌症治疗的靶点。在这里，我们研究了 COX-2 与乳腺癌生存的关联，以及肿瘤雌激素和 HER2 受体状态以及 Akt 通路激活如何影响这种关联。采用免疫组织化学方法分析 248 例乳腺癌中肿瘤 COX-2、HER2 和雌激素受体 α (ER) 的表达以及 Akt、BAD 和 caspase-9 的磷酸化。 Spearman相关性和多变量逻辑回归分析用于检查COX-2与肿瘤特征之间的关系。 Kaplan-Meier 生存率和多变量 Cox 比例风险回归分析用于检查 COX-2 与疾病特异性生存率之间的关系。 COX-2 与 ER 阴性乳腺癌结果显着相关 [风险比 (HR) = 2.72； 95%置信区间（CI），1.36-5.41；比较高与低 COX-2] 和 HER2 过表达乳腺癌（HR = 2.84；95% CI，1.07-7.52）。然而，在 ER 阴性和 HER2 阳性患者中，与 COX-2 升高相关的生存不良风险最高（HR = 5.95；95% CI，1.01-34.9）。值得注意的是，ER 阴性和 HER2 阳性肿瘤中的 COX-2 表达与 Akt 和两个 Akt 靶点（Ser136 处的 BAD 和 Ser196 处的 caspase-9）磷酸化的增加显着相关。 ER 阴性和 HER2 阳性乳腺肿瘤中 COX-2 的上调与 Akt 通路激活相关，是预后不良的标志。研究结果表明，COX-2 特异性抑制剂和 Akt 通路抑制剂可能在 ER 阴性和 HER2 阳性乳腺癌亚型中作为抗癌药物发挥协同作用。
Inducible cyclooxgenase-2 (COX-2) is commonly overexpressed in breast tumors and is a target for cancer therapy. Here, we studied the association of COX-2 with breast cancer survival and how this association is influenced by tumor estrogen and HER2 receptor status and Akt pathway activation. Tumor COX-2, HER2 and estrogen receptor α (ER) expression and phosphorylation of Akt, BAD, and caspase-9 were analyzed immunohistochemically in 248 cases of breast cancer. Spearman's correlation and multivariable logistic regression analyses were used to examine the relationship between COX-2 and tumor characteristics. Kaplan-Meier survival and multivariable Cox proportional hazards regression analyses were used to examine the relationship between COX-2 and disease-specific survival. COX-2 was significantly associated with breast cancer outcome in ER-negative [Hazard ratio (HR) = 2.72; 95% confidence interval (CI), 1.36-5.41; comparing high versus low COX-2] and HER2 overexpressing breast cancer (HR = 2.84; 95% CI, 1.07-7.52). However, the hazard of poor survival associated with increased COX-2 was highest among patients who were both ER-negative and HER2-positive (HR = 5.95; 95% CI, 1.01-34.9). Notably, COX-2 expression in the ER-negative and HER2-positive tumors correlated significantly with increased phosphorylation of Akt and of the two Akt targets, BAD at Ser136 and caspase-9 at Ser196. Up-regulation of COX-2 in ER-negative and HER2-positive breast tumors is associated with Akt pathway activation and is a marker of poor outcome. The findings suggest that COX-2-specific inhibitors and inhibitors of the Akt pathway may act synergistically as anticancer drugs in the ER-negative and HER2-positive breast cancer subtype.
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影响因子：
8
作者：
Knuefermann, C;Lu, Y;Fan, Z
通讯作者：
Fan, Z
影响因子：
3.1
作者：
Offersen, Birgitte Vrou;Alsner, Jan;Overgaard, Jens
通讯作者：
Overgaard, Jens
影响因子：
2.4
作者：
Modi, S;DiGiovanna, MP;Seidman, AD
通讯作者：
Seidman, AD
影响因子：
4.8
作者：
Andjelkovic, M;Alessi, DR;Hemmings, BA
通讯作者：
Hemmings, BA
DOI：
10.1093/jnci/djj245
发表时间：
2006-07-05
期刊：
JOURNAL OF THE NATIONAL CANCER INSTITUTE
影响因子：
--
作者：
Boersma, Brenda J.;Howe, Tiffany M.;Ambs, Stefan
通讯作者：
Ambs, Stefan