Global characterization of the SRC-1 transcriptome identifies ADAM22 as an ER-independent mediator of endocrine-resistant breast cancer.
Global characterization of the SRC-1 transcriptome identifies ADAM22 as an ER-independent mediator of endocrine-resistant breast cancer.
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SRC-1转录组的全球表征将ADAM22鉴定为抗内分泌耐药性乳腺癌的ER独立介质。
DOI：
10.1158/0008-5472.can-11-1976
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发表时间：
2012-01-01
期刊：
影响因子：
11.2
通讯作者：
Young LS
中科院分区：
文献类型：
--
作者：
McCartan D;Bolger JC;Fagan A;Byrne C;Hao Y;Qin L;McIlroy M;Xu J;Hill AD;Gaora PÓ;Young LS
乳腺癌对内分泌治疗的抵抗是由于细胞可塑性的增加而导致激素非依赖性肿瘤的出现。类固醇共激活蛋白SRC-1通过与发育蛋白和其他非类固醇转录因子的相互作用，驱动这种肿瘤的适应性。在这项发现研究中，我们发现ADAM22是ADAM家族去整合素家族中的一个非蛋白水解酶成员，是SRC-1的一个直接ER非依赖性靶标。我们通过分子、细胞和体内研究证实SRC-1是ADAM22的调节因子。在人乳腺癌小鼠移植模型中，ADAM22在细胞迁移和分化中发挥作用，与内分泌敏感肿瘤相比，其水平升高。临床上，ADAM22被发现是无病生存率较低的独立预测因子。综上所述，我们的发现表明，SRC-1将类固醇敏感的肿瘤切换到类固醇耐药状态，其中SRC-1靶基因ADAM22起着关键作用，这表明该分子是一种预后和治疗药物靶点，可能有助于改善内分泌抵抗型乳腺癌的治疗。
The development of breast cancer resistance to endocrine therapy results from an increase in cellular plasticity that permits the emergence of a hormone independent tumor. The steroid coactivator protein SRC-1, through interactions with developmental proteins and other non-steroidal transcription factors, drives this tumor adaptability. In this discovery study we identified ADAM22, a non-protease member of the ADAM family of disintegrins, as a direct ER-independent target of SRC-1. We confirmed SRC-1 as a regulator of ADAM22 by molecular, cellular and in vivo studies. ADAM22 functioned in cellular migration and differentiation and its levels were increased endocrine resistant tumors compared to endocrine sensitive tumors in a mouse xenograft models of human breast cancer. Clinically ADAM22 was found to serve as an independent predictor of poor disease-free survival. Taken together, our findings suggest that SRC-1 switches steroid-responsive tumors to a steroid resistant state in which the SRC-1 target gene ADAM22 has a critical role, suggesting this molecule as a prognostic and therapeutic drug target that could help improve the treatment of endocrine-resistant breast cancer.