Increased Expression of P-Glycoprotein Is Associated with Doxorubicin Chemoresistance in the Metastatic 4T1 Breast Cancer Model
Increased Expression of P-Glycoprotein Is Associated with Doxorubicin Chemoresistance in the Metastatic 4T1 Breast Cancer Model
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DOI：
10.1016/j.ajpath.2010.10.029
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发表时间：
2011-02-01
影响因子：
6
通讯作者：
Dash, Srikanta
中科院分区：
文献类型：
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作者：
Bao, Lili;Haque, Aliyya;Dash, Srikanta
耐药性的发展是乳腺癌治疗失败的主要原因之一。本研究的目的是使用高转移性4 T1乳腺癌模型来了解化疗耐药机制，该模型模拟人类IV期乳腺癌。用多柔比星或5-FU处理的转移性4 T1乳腺癌细胞系显示出浓度依赖性的细胞增殖减少，诱导G2期生长停滞（多柔比星）或G1期生长停滞（5-FU）。与5-FU或环磷酰胺相比，阿霉素治疗部分抑制了4 T1乳腺癌细胞在肺、心脏、肝脏和骨中的多器官转移。我们从阿霉素耐药转移性肿瘤（细胞系4 T1-R）中分离并鉴定了4 T1乳腺癌细胞。耐药4 T1乳腺肿瘤的多器官转移对阿霉素治疗完全耐药。我们的研究结果表明，多柔比星是专门定位在耐药4 T1乳腺癌细胞的细胞质中，它不能到达细胞核，因为核表达的P-糖蛋白的增加。用维拉帕米（一种P-糖蛋白的一般抑制剂）预处理阿霉素耐药的4 T1-R乳腺癌细胞，增加阿霉素的核转位和细胞毒性。因此，由于P-糖蛋白表达增加导致的阿霉素核转位受损与高转移性4 T1乳腺癌的阿霉素耐药相关。(Am J Pathol 2011，178：838-852; 10.1016/j.ajpath.2010.10.029）
Development of drug resistance is one of the major causes of breast cancer treatment failure. The goal of this study was to understand the chemoresistance mechanism using the highly metastatic 4T1 breast cancer model, which emulates stage IV breast cancer in humans. The metastatic 4T1 breast cancer cell line treated with either doxorubicin or 5-FU showed a concentration-dependent reduced cell proliferation, with induced G2-phase growth arrest (doxorubicin) or G1-phase growth arrest (5-FU). Doxorubicin treatment partially suppressed the multiorgan metastasis of 4T1 breast cancer cells in the lung, heart, liver, and bone, compared with either 5-FU or cyclophosphamide. We isolated and characterized 4T1 breast cancer cells from doxorubicin-resistant metastatic tumors (cell line 4T1-R). Multiorgan metastasis of drug-resistant 4T1 breast tumors was totally resistant to doxorubicin treatment. Our results indicate that doxorubicin is localized exclusively in the cytoplasm of resistant 4T1 breast cancer cells and that it cannot reach the nucleus because of increased nuclear expression of P-glycoprotein. Pretreatment of doxorubicin-resistant 4T1-R breast cancer cells with verapamil, a general inhibitor of P-glycoprotein, increased nuclear translocation of doxorubicin and cellular cytotoxicity. Thus, impaired nuclear translocation of doxorubicin due to increased expression of P-glycoprotein is associated with doxorubicin resistance of highly metastatic 4T1 breast cancer. (Am J Pathol 2011, 178:838-852; 10.1016/j.ajpath.2010.10.029)