Glucocorticoid receptor (GR) is involved in the transcriptional regulation of genes that are important for various biological functions, including tumor growth and metastatic progression. However, the cellular and biological effects of GR remain poorly understood. Here, we investigated the role of GR and its underlying mechanism in mediating breast cancer cell survival and metastasis. We observed that the GR levels were increased in drug-resistant breast cancer cells and in metastatic breast cancer samples. GR promoted tumor cell invasion and lung metastasis in vivo. The GR expression levels were negatively correlated with the survival rates of breast cancer patients. Both ectopic expression and knockdown of GR revealed that GR is a strong inducer of epithelial-to-mesenchymal transition (EMT), which is consistent with its effects on cell survival and metastasis. GR suppressed the expression of insulin receptor substrate 1 (IRS-1) by acting as an IRS-1 transcriptional repressor. In addition, GR has an opposite effect on the expression levels of IRS-2, indicating that GR is able to differentially regulate the IRS-1 and IRS-2 expression. The cellular and biological effects elicited by GR were consistent with the reduced levels of IRS-1 observed in cancer cells, and GR-mediated IRS-1 suppression activated the ERK2 MAP kinase pathway, which is required for GR-mediated EMT. Taken together, our results indicate that GR-IRS-1 signaling axis plays an essential role in regulating the survival, invasion, and metastasis of breast cancer cells.

中文翻译：

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糖皮质激素受体-IRS-1轴控制着EMT和乳腺癌的转移。

糖皮质激素受体（GR）参与基因的转录调控，这些基因对于各种生物学功能（包括肿瘤生长和转移性进展）很重要。但是，对GR的细胞和生物学作用仍然知之甚少。在这里，我们调查了遗传资源及其在介导乳腺癌细胞存活和转移中的潜在机制的作用。我们观察到耐药性乳腺癌细胞和转移性乳腺癌样品中的GR水平升高。GR促进体内肿瘤细胞的侵袭和肺转移。GR表达水平与乳腺癌患者的存活率负相关。异位表达和GR的敲除都表明GR是上皮到间质转化（EMT）的强大诱导剂，这与其对细胞存活和转移的影响是一致的。GR通过充当IRS-1转录阻遏物来抑制胰岛素受体底物1（IRS-1）的表达。此外，GR对IRS-2的表达水平有相反的影响，表明GR能够差异调节IRS-1和IRS-2的表达。GR引起的细胞和生物学效应与癌细胞中观察到的IRS-1降低水平一致，并且GR介导的IRS-1抑制激活了GR介导的EMT所需的ERK2 MAP激酶途径。两者合计，我们的结果表明GR-IRS-1信号轴在调节乳腺癌细胞的存活，侵袭和转移中起着至关重要的作用。GR通过充当IRS-1转录阻遏物来抑制胰岛素受体底物1（IRS-1）的表达。此外，GR对IRS-2的表达水平有相反的影响，表明GR能够差异调节IRS-1和IRS-2的表达。GR引起的细胞和生物学效应与癌细胞中观察到的IRS-1降低水平一致，并且GR介导的IRS-1抑制激活了GR介导的EMT所需的ERK2 MAP激酶途径。两者合计，我们的结果表明GR-IRS-1信号轴在调节乳腺癌细胞的存活，侵袭和转移中起着至关重要的作用。GR通过充当IRS-1转录阻遏物来抑制胰岛素受体底物1（IRS-1）的表达。此外，GR对IRS-2的表达水平有相反的影响，表明GR能够差异调节IRS-1和IRS-2的表达。GR引起的细胞和生物学效应与癌细胞中观察到的IRS-1降低水平一致，并且GR介导的IRS-1抑制激活了GR介导的EMT所需的ERK2 MAP激酶途径。两者合计，我们的结果表明GR-IRS-1信号轴在调节乳腺癌细胞的存活，侵袭和转移中起着至关重要的作用。表明GR能够差异调节IRS-1和IRS-2的表达。GR引起的细胞和生物学效应与癌细胞中观察到的IRS-1降低水平一致，并且GR介导的IRS-1抑制激活了GR介导的EMT所需的ERK2 MAP激酶途径。两者合计，我们的结果表明GR-IRS-1信号轴在调节乳腺癌细胞的存活，侵袭和转移中起着至关重要的作用。表明GR能够差异调节IRS-1和IRS-2的表达。GR引起的细胞和生物学效应与癌细胞中观察到的IRS-1降低水平一致，并且GR介导的IRS-1抑制激活了GR介导的EMT所需的ERK2 MAP激酶途径。两者合计，我们的结果表明GR-IRS-1信号轴在调节乳腺癌细胞的存活，侵袭和转移中起着至关重要的作用。