Dynamic emergence of the mesenchymal CD44posCD24neg/low phenotype in HER2-gene amplified breast cancer cells with de novo resistance to trastuzumab (Herceptin)
Dynamic emergence of the mesenchymal CD44posCD24neg/low phenotype in HER2-gene amplified breast cancer cells with de novo resistance to trastuzumab (Herceptin)
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DOI：
10.1016/j.bbrc.2010.05.041
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发表时间：
2010-06-18
影响因子：
3.1
通讯作者：
Menendez, Javier A.
中科院分区：
文献类型：
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作者：
Oliveras-Ferraros, Cristina;Vazquez-Martin, Alejandro;Menendez, Javier A.
越来越多的证据表明，含有潜在乳腺癌（BC）干细胞的CD 44（阳性）/CD 24（阴性/低）细胞群的出现可以解释BC对HER 2靶向治疗的临床耐药性。我们研究了抗HER 2单克隆抗体曲妥珠单抗（Tzb;赫赛汀）的新发难治性是否可能与HER 2阳性BC中间充质CD 44（阳性）/CD 24（阴性/低）表型的动态调节有关。我们观察到Tzb-难治性JIMT-1 BC细胞亚群显示出CD 44（阳性）/CD 24（阴性/低）-表面标志物随时间转换。发现低传代JIMT-1细胞培养物自发含有接近10%的携带CD 44（阳性）/CD 24（阴性/低）免疫表型的细胞。晚代（>60）JIMT-1培养物积累了类似于80%的⑶ 44（正）/⑶ 24（负/低）细胞，并且非常类似于在HER 2阴性MDA-MB-231间充质BC细胞中组成性存在的⑶ 44（正）/⑶ 24（负/低）富集的细胞群体（类似于85%）。间充质标志物的动态表达不限于CD 44/CD 24，因为高传代的JIMT-1细胞也表现出降低的HER 2蛋白表达和促侵袭/转移趋化因子和金属蛋白酶的过度分泌。因此，晚期传代JIMT-1细胞在塑料、胶原和纤连蛋白基质中显示出加剧的致迁移表型。有效驱动CD 44（阳性）/CD 24（阴性/低）间充质表型出现的内在遗传可塑性可能是携带HER 2基因扩增的基底细胞样BC对HER 2靶向治疗产生新发耐药性的原因。(C)2010年爱思唯尔公司All rights reserved.
Evidence is mounting that the occurrence of the CD44(pos)/CD24(neg/low) cell population, which contains potential breast cancer (BC) stem cells, could explain BC clinical resistance to HER2-targeted therapies. We investigated whether de novo refractoriness to the anti-HER2 monoclonal antibody trastuzumab (Tzb; Herceptin) may relate to the dynamic regulation of the mesenchymal CD44(pos)/CD24(neg/low) phenotype in HER2-positive BC. We observed that the subpopulation of Tzb-refractory JIMT-1 BC cells exhibiting CD44(pos)/CD24(neg/low)-surface markers switched with time. Low-passage JIMT-1 cell cultures were found to spontaneously contain similar to 10% of cells bearing the CD44(pos)/CD24(neg/low) immunophenotype. Late-passage (>60) JIMT-1 cultures accumulated similar to 80% of CD44(pos)/CD24(neg/low)cells and closely resembled the CD44(pos)/CD24(neg/low)-enriched (similar to 85%) cell population constitutively occurring in HER2-negative MDA-MB-231 mesenchymal BC cells. Dynamic expression of mesenchymal markers was not limited to CD44/CD24 because high-passages of JIMT-1 cells exhibited also reduced expression of the HER2 protein and over-secretion of pro-invasive/metastatic chemokines and metalloproteases. Accordingly, late-passage JIMT-1 cells displayed an exacerbated migratogenic phenotype in plastic, collagen, and fibronectin substrates. Intrinsic genetic plasticity to efficiently drive the emergence of the CD44(pos)/CD24(neg/low) mesenchymal phenotype may account for de novo resistance to HER2 targeting therapies in basal-like BC carrying HER2 gene amplification. (C) 2010 Elsevier Inc. All rights reserved.