Cufi Silvia, Corominas-Faja Bruna, Vazquez-Martin Alejandro, Oliveras-Ferraros Christina, Dorca Joan, Bosch-Barrera Joaquim, Martin-Castillo Begoña, Menendez Javier A
Translational Research Laboratory, Catalan Institute of Oncology (ICO), Girona, Spain.
Oncotarget. 2012 Apr;3(4):395-8. doi: 10.18632/oncotarget.488.
Trastuzumab-refractory breast cancer stem cells (CSCs) could also explain the high rate of primary resistance to single-agent trastuzumab in HER2 gene-amplified breast cancer patients. The identification of agents with strong selective toxicity for trastuzumab-resistant breast CSCs may have tremendous relevance for how HER2+ breast cancer patients should be treated. Using the human breast cancer cell line JIMT-1, which was established from the pleural metastasis of a patient who was clinically resistant to trastuzumab ab initio, we examined whether preferential killing of the putative CD44+CD24-/low breast CSC population might be sufficient to overcome primary resistance to trastuzumab in vivo. Because recent studies have shown that the anti-diabetic biguanide metformin can exert antitumor effects by targeted killing of CSC-like cells, we explored whether metformin's ability to preferentially kill breast cancer initiating CD44+CD24-/low cells may have the potential to sensitize JIMT-1 xenograft mouse models to trastuzumab. Upon isolation for breast cancer initiating CD44+CD24-/low cells by employing magnetic activated cell sorting, we observed the kinetics of metformin-induced killing drastically varied among CSC and non-CSC subpopulations. Metformin's cell killing effect increased dramatically by more than 10-fold in CD44+CD24-/low breast CSC cells compared to non-CD44+CD24-/low immunophenotypes. While seven-weeks treatment length with trastuzumab likewise failed to reduce tumor growth of JIMT-1 xenografts, systemic treatment with metformin as single agent resulted in a significant two-fold reduction in tumor volume. When trastuzumab was combined with concurrent metformin, tumor volume decreased sharply by more than four-fold. Given that metformin-induced preferential killing of breast cancer initiating CD44+CD24-/low subpopulations is sufficient to overcome in vivo primary resistance to trastuzumab, the incorporation of metformin into trastuzumab-based regimens may provide a valuable strategy for treatment of HER2+ breast cancer patients.
曲妥珠单抗难治性乳腺癌干细胞（CSCs）也可以解释HER2基因扩增的乳腺癌患者对单药曲妥珠单抗原发性耐药的高发生率。鉴定对曲妥珠单抗耐药的乳腺癌CSCs具有强选择性毒性的药物，对于HER2阳性乳腺癌患者的治疗方式可能具有重大意义。利用人乳腺癌细胞系JIMT-1（该细胞系源自一名临床上从一开始就对曲妥珠单抗耐药的患者的胸膜转移灶），我们研究了优先杀伤假定的CD44+CD24-/低乳腺癌CSC群体是否足以在体内克服对曲妥珠单抗的原发性耐药。由于最近的研究表明，抗糖尿病双胍类药物二甲双胍可通过靶向杀伤CSC样细胞发挥抗肿瘤作用，我们探讨了二甲双胍优先杀伤乳腺癌起始CD44+CD24-/低细胞的能力是否有可能使JIMT-1异种移植小鼠模型对曲妥珠单抗敏感。在用磁珠分选法分离出乳腺癌起始CD44+CD24-/低细胞后，我们观察到二甲双胍诱导的杀伤动力学在CSC和非CSC亚群之间有很大差异。与非CD44+CD24-/低免疫表型相比，二甲双胍对CD44+CD24-/低乳腺癌CSC细胞的杀伤作用显著增加了10倍以上。虽然曲妥珠单抗治疗7周同样未能减少JIMT-1异种移植瘤的生长，但单药二甲双胍全身治疗使肿瘤体积显著减少了两倍。当曲妥珠单抗与二甲双胍联合使用时，肿瘤体积急剧减少了四倍多。鉴于二甲双胍诱导的对乳腺癌起始CD44+CD24-/低亚群的优先杀伤足以克服体内对曲妥珠单抗的原发性耐药，将二甲双胍纳入基于曲妥珠单抗的治疗方案可能为HER2阳性乳腺癌患者的治疗提供一种有价值的策略。
