Dynamic emergence of the mesenchymal CD44^posCD24^neg/low phenotype in HER2-gene amplified breast cancer cells with de novo resistance to trastuzumab (Herceptin)

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• 作者：Cristina Oliveras-Ferraros ; Alej ; ro Vazquez-Martin ; Begoñ ; a Martin-Castillo ; Silvia Cufí ; Sonia Del Barco ; Eugeni Lopez-Bonet ; Joan Brunet ; Javier A. Menendez
• 关键词：HER2 ; Trastuzumab ; Stem cells ; Basal-like ; Breast cancer
• 刊名：Biochemical and Biophysical Research Communications
• 出版年：2010
• 出版时间：18 June 2010
• 年：2010
• 卷：397
• 期：1
• 页码：27-33
• 全文大小：3113 K

文摘

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 10 % of cells bearing the CD44^pos/CD24^neg/low immunophenotype. Late-passage (>60) JIMT-1 cultures accumulated 80 % of CD44^pos/CD24^neg/low cells and closely resembled the CD44^pos/CD24^neg/low-enriched (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.