Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, 200040, China.
Mol Biol Rep. 2012 May;39(5):5465-71. doi: 10.1007/s11033-011-1347-4. Epub 2011 Dec 17.
Despite the improvement of strategies against cancer therapy, the multidrug resistance (MDR)is the critical problem for successful cancer therapy. Recurrent cancers after initial treatment with chemotherapy are generally refractory to second treatments with these anticancer therapies. Therefore, it is necessary to elucidate the therapy-resistant mechanism for development of effective therapeutic modalities against tumors. Here we demonstrate a phase-specific chemotherapy resistance due to epidermal growth factor receptor (EGFR) in human breast cancer cells. Thymidine-induced G1-arrested cultures showed upregulated chemosensitivity, whereas S-phase arrested cells were more resistant to chemotherapeutic agents. Overexpression of EGFR promoted the MDR phenotypes in breast cancer cells via accelerating the G1/S phase transition, whereas depletion of EGFR exerted the opposite effects. Furthermore, CyclinD1, a protein related to cell cycle, was demonstrated to be involved in above EGFR-mediated effects since EGFR increased the expression of CyclinD1, and the specific RNA interference against CyclinD1 could primarily abolish the EGFR-induced MDR phenotypes. These data provide new insights into the mode by which MDR breast cancers evade cytoxic attacks from chemotherapeutic agents and also suggest a role for EGFR-CyclinD1 axis in this process.
尽管癌症治疗策略有所改进，但多药耐药（MDR）仍是癌症治疗成功的关键问题。初始化疗后复发的癌症通常对这些抗癌治疗的第二次治疗具有抗药性。因此，有必要阐明治疗耐药机制，以开发针对肿瘤的有效治疗方法。在这里，我们证明了人乳腺癌细胞中表皮生长因子受体（EGFR）导致的特定化疗耐药性。胸苷诱导的 G1 期阻滞培养物显示出化学增敏性增加，而 S 期阻滞细胞对化疗药物的抵抗力更强。EGFR 的过表达通过加速 G1/S 期转变促进了乳腺癌细胞的多药耐药表型，而 EGFR 的耗竭则产生了相反的效果。此外，细胞周期相关蛋白 CyclinD1 被证明参与了上述由 EGFR 介导的作用，因为 EGFR 增加了 CyclinD1 的表达，而针对 CyclinD1 的特异性 RNA 干扰可以主要消除 EGFR 诱导的多药耐药表型。这些数据为 MDR 乳腺癌逃避化疗药物细胞毒性攻击的模式提供了新的见解，并表明 EGFR-CyclinD1 轴在这一过程中起作用。
