Abstract
BackgroundThe malignant potential of triple negative breast cancer (TNBC) is also dependent on a sub-population of cells with a stem-like phenotype. Among the cancer stem cell markers, CD133 and EpCAM strongly correlate with breast tumor aggressiveness, suggesting that simultaneous targeting of the two surface antigens may be beneficial in treatment of TNBC. Since in TNBC-derived cells we demonstrated that PLC-β2 induces the conversion of CD133high to CD133low cells, here we explored its possible role in down-modulating the expression of both CD133 and EpCAM and, ultimately, in reducing the number of TNBC cells with a stem-like phenotype.MethodsA magnetic step-by-step cell isolation with antibodies directed against CD133 and/or EpCAM was performed on the TNBC-derived MDA-MB-231 cell line. In the same cell model, PLC-β2 was over-expressed or down-modulated and cell proliferation and invasion capability were evaluated by Real-time cell assays. The surface expression of CD133, EpCAM and CD44 in the different experimental conditions were measured by multi-color flow cytometry immunophenotyping.ResultsA CD133+/EpCAM+ sub-population with high proliferation rate and invasion capability is present in the MDA-MB-231 cell line. Over-expression of PLC-β2 in CD133+/EpCAM+ cells reduced the surface expression of both CD133 and EpCAM, as well as proliferation and invasion capability of this cellular subset. On the other hand, the up-modulation of PLC-β2 in the whole MDA-MB-231 cell population reduced the number of cells with a CD44+/CD133+/EpCAM+ stem-like phenotype.ConclusionsSince selective targeting of the cells with the highest aggressive potential may have a great clinical importance for TNBC, the up-modulation of PLC-β2, reducing the number of cells with a stem-like phenotype, may be a promising goal for novel therapies aimed to prevent the progression of aggressive breast tumors.
Highlights
The malignant potential of triple negative breast cancer (TNBC) is dependent on a sub-population of cells with a stem-like phenotype
A MDA-MB-231 sub-population expressing high surface levels of CD133 and Epithelial cell adhesion molecule (EpCAM) shows elevated proliferation and invasion capability By means of a cytofluorimetrical approach, we confirmed the existence of cells expressing CD133 at surface level in the highly tumorigenic Triple-negative breast cancer (TNBC) derived MDA-MB-231 cell line and we revealed that almost 90% of cells result EpCAM+ (Fig. 1a)
At variance with hepatocellular carcinoma (HCC), in which the features of cells with different CD133/EpCAM phenotypes were subjected to both in vitro and in vivo characterization [26], no information is available on TNBC derived cells showing variable surface levels of the two antigens
Summary
The malignant potential of triple negative breast cancer (TNBC) is dependent on a sub-population of cells with a stem-like phenotype. A toxin-based system to simultaneously target CD133 and EpCAM in the same cell was developed in different carcinoma models, including inflammatory breast carcinoma, showing a potent inhibition of proliferation in vitro and the regression of HNSCC (Head and neck squamous cell carcinoma) in vivo [15] Despite these encouraging results, the use on human tumors is far for being advantageous, due to the high costs of toxin generation and, more importantly, to the off-target effects or to the generation of anti-toxin antibodies having adverse effects against extended treatments [16]
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