Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Cancer Cell. 2010 Nov 16;18(5):423-35. doi: 10.1016/j.ccr.2010.10.025.
We found that the receptor for erythropoietin (EpoR) is coexpressed with human epidermal growth factor receptor-2 (HER2) in a significant percentage of human breast tumor specimens and breast cancer cell lines. Exposure of HER2 and EpoR dual-positive breast cancer cells to recombinant human erythropoietin (rHuEPO) activated cell signaling. Concurrent treatment of the cells with rHuEPO and trastuzumab reduced the cells' response to trastuzumab both in vitro and in vivo. We identified Jak2-mediated activation of Src and inactivation of PTEN as underlying mechanisms through which rHuEPO antagonizes trastuzumab-induced therapeutic effects. Furthermore, we found that compared with administration of trastuzumab alone, concurrent administration of rHuEPO and trastuzumab correlated with shorter progression-free and overall survival in patients with HER2-positive metastatic breast cancer.
我们发现，促红细胞生成素受体（EpoR）在相当一部分人类乳腺癌标本和乳腺癌细胞系中与人类表皮生长因子受体-2（HER2）共表达。HER2 和 EpoR 双阳性乳腺癌细胞暴露于重组人促红细胞生成素（rHuEPO）可激活细胞信号转导。同时用 rHuEPO 和曲妥珠单抗治疗这些细胞，可在体外和体内降低细胞对曲妥珠单抗的反应。我们确定 Jak2 介导的Src 激活和 PTEN 失活是 rHuEPO 拮抗曲妥珠单抗诱导的治疗效果的潜在机制。此外，我们发现与单独使用曲妥珠单抗相比，HER2 阳性转移性乳腺癌患者同时使用 rHuEPO 和曲妥珠单抗与无进展生存期和总生存期缩短相关。
