Ceramide kinase promotes tumor cell survival and mammary tumor recurrence.
Ceramide kinase promotes tumor cell survival and mammary tumor recurrence.
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DOI：
10.1158/0008-5472.can-14-1292
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发表时间：
2014-11-01
期刊：
影响因子：
11.2
通讯作者：
Chodosh LA
中科院分区：
文献类型：
--
作者：
Payne AW;Pant DK;Pan TC;Chodosh LA
复发性乳腺癌通常是一种无法治愈的疾病，因此，这种疾病造成的死亡比例过高。复发性乳腺癌起源于弥散性肿瘤细胞（dtc），这些细胞在辅助或新辅助治疗后存活，治疗后检测到dtc的患者复发的风险大大增加。因此，确定有助于治疗后乳腺癌细胞存活的途径可能有助于开发更有效的治疗方法，减少残留疾病的负担，从而降低乳腺癌复发的风险。我们现在报道，神经酰胺激酶（Cerk）在HER2/neu通路抑制后的乳腺肿瘤复发中是必需的，并且在多种乳腺癌基因工程小鼠模型的肿瘤复发过程中自发上调。我们发现HER2/neu下调或阿霉素治疗后，肿瘤细胞中Cerk迅速上调，HER2/neu下调后肿瘤细胞存活需要Cerk。与我们在小鼠模型中的观察结果一致，对2200多名患者基因表达谱的分析显示，CERK表达升高与乳腺癌女性复发风险增加有关。此外，尽管CERK表达与侵袭性乳腺癌亚型相关，包括那些ER -、HER2+、基底样或高分级的乳腺癌，但其与不良临床结果的关联与这些临床病理变量无关。总之，我们的研究结果确定了Cerk在乳腺癌复发中的功能作用，并建议针对这种促生存途径的药物的临床应用。
Recurrent breast cancer is typically an incurable disease and, as such, is disproportionately responsible for deaths from this disease. Recurrent breast cancers arise from the pool of disseminated tumor cells (DTCs) that survive adjuvant or neoadjuvant therapy, and patients with detectable DTCs following therapy are at substantially increased risk for recurrence. Consequently, the identification of pathways that contribute to the survival of breast cancer cells following therapy could aid in the development of more effective therapies that decrease the burden of residual disease and thereby reduce the risk of breast cancer recurrence. We now report that Ceramide Kinase (Cerk) is required for mammary tumor recurrence following HER2/neu pathway inhibition and is spontaneously up-regulated during tumor recurrence in multiple genetically engineered mouse models for breast cancer. We find that Cerk is rapidly up-regulated in tumor cells following HER2/neu down-regulation or treatment with Adriamycin and that Cerk is required for tumor cell survival following HER2/neu down-regulation. Consistent with our observations in mouse models, analysis of gene expression profiles from over 2,200 patients revealed that elevated CERK expression is associated with an increased risk of recurrence in women with breast cancer. Additionally, although CERK expression is associated with aggressive subtypes of breast cancer, including those that are ER–, HER2+, basal-like, or high grade, its association with poor clinical outcome is independent of these clinicopathological variables. Together, our findings identify a functional role for Cerk in breast cancer recurrence and suggest the clinical utility of agents targeted against this pro-survival pathway.