Autocrine/paracrine mechanism of interleukin-17B receptor promotes breast tumorigenesis through NF-κB-mediated antiapoptotic pathway
Autocrine/paracrine mechanism of interleukin-17B receptor promotes breast tumorigenesis through NF-κB-mediated antiapoptotic pathway
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DOI：
10.1038/onc.2013.268
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发表时间：
2014-06-05
期刊：
影响因子：
8
通讯作者：
Lee, W-H
中科院分区：
文献类型：
--
作者：
Huang, C-K;Yang, C-Y;Lee, W-H
膜受体功能的获得是癌细胞利用的一种有利于自身生长和生存的良好策略。HER2的过表达已被发现作为开发曲妥珠单抗治疗20-25%乳腺癌的靶标。然而，从那时起，很少或没有发现其他膜受体作为乳腺癌治疗的潜在靶点有用。在这里，我们发现白细胞介素-17受体B （IL-17RB）及其配体IL-17B的信号扩增促进了乳腺癌细胞的致瘤性，并阻碍了永生化正常乳腺上皮细胞的腺泡形成。通过IL-17RB传递的外部信号激活核因子κ B上调抗凋亡因子Bcl-2，诱导依托泊苷耐药。在乳腺癌患者中，IL-17RB表达升高与预后不良的相关性强于HER2。有趣的是，IL-17RB和HER2高表达的乳腺癌患者生存率最短。在曲妥珠单抗耐药乳腺癌细胞中，IL-17RB的缺失显著降低了其致瘤活性，提示IL-17RB和HER2在乳腺癌发生中具有独立的作用。此外，用特异性针对IL-17RB或IL-17B的抗体治疗可有效降低乳腺癌细胞的致瘤性。这些结果表明，扩增的IL-17RB/IL-17B信号通路可能作为开发治疗IL-17RB相关乳腺癌的治疗靶点。
Gain of function of membrane receptor was a good strategy exploited by cancer cells to benefit own growth and survival. Overexpression of HER2 has been found to serve as a target for developing trastuzumab to treat 20-25% of breast cancer. However, little or none of the other membrane receptor was found to be useful as a potential target for breast cancer treatment since then. Here, we showed that amplified signaling of interleukin-17 receptor B (IL-17RB) and its ligand IL-17B promoted tumorigenicity in breast cancer cells and impeded acinus formation in immortalized normal mammary epithelial cells. External signal transmitted through IL-17RB activated nuclear factor-kappa B to upregulate antiapoptotic factor Bcl-2 and induced etoposide resistance. Elevated expression of IL-17RB had a stronger correlation with poor prognosis than HER2 in breast cancer patients. Interestingly, breast cancer patients with high expression of IL-17RB and HER2 had the shortest survival rate. Depletion of IL-17RB in trastuzumab-resistant breast cancer cells significantly reduced their tumorigenic activity, suggesting that IL-17RB and HER2 have an independent role in breast carcinogenesis. Furthermore, treatment with antibodies specifically against IL-17RB or IL-17B effectively attenuated tumorigenicity of breast cancer cells. These results suggest that the amplified IL-17RB/IL-17B signaling pathways may serve as a therapeutic target for developing treatment to manage IL-17RB-associated breast cancer.