Exploring the effects of inhibiting miR-10b on breast cancer stemness and metastasis.

Abstract

e13084 Background: There are currently limited effective therapeutic options for metastatic breast cancer, and none target the metastatic process. MiR-10b is a major driver of breast cancer cell invasion and migration. Our lab has demonstrated its importance in metastatic cell viability, positioning miR-10b as a target for metastatic breast cancer. Our previous studies demonstrated that delivery of a novel therapeutic consisting of antisense anti-miR-10b oligomers conjugated to magnetic nanoparticles (termed MN-anti-miR10b) prevented metastases in vivo. These studies led us to hypothesize that MN-anti-miR10b affects the viability of a stem cell-like population of cells within primary tumors that otherwise would have formed metastases. Here, we investigate the relationship between miR-10b and breast cancer cell stemness and the effects of miR-10b inhibition by MN-anti-miR10b on breast cancer cell stemness. Methods: MDA-MB-231 breast cancer cells were sorted based on surface markers into stem-like (CD44+/CD24-) and non-stem-like (CD44-/CD24-) populations, and their miR-10b expression levels were quantitated. Then, unsorted MDA-MB-231 cells were treated with MN-anti-miR10b to determine the effects of miR-10b inhibition on the expression of EPCAM, a marker for cancer cell stemness. Lastly, MCF-7 breast cancer cells were cultured in mammosphere medium (which selects for stem-like cells and induces spheroid formation) and treated with MN-anti-miR10b to establish the phenotypic effect of miR-10b inhibition on cancer cell stemness. Results: We found that stem-like MDA-MB-231 cells displayed >2-fold miR-10b expression compared to non-stem-like cells. Accordingly, alongside a 70% reduction in miR-10b expression, treatment of MDA-MB-231 cells with MN-anti-miR10b reduced EPCAM expression by 65%. Treatment of MCF-7 spheroids with MN-anti-miR10b resulted in significantly greater cell dissociation from the spheroid compared to controls. Conclusions: These results support the hypothesis that inhibition of miR-10b with MN-anti-miR10b inhibits breast cancer cell stemness. This provides an explanation for the therapeutic efficacy of MN-anti-miR10b observed in mouse breast cancer metastasis models. Future studies will further investigate this relationship and shed light on how miR-10b can be optimally targeted to treat metastatic breast cancer in humans.

Self-Renewal Inhibition in Breast Cancer Stem Cells: Moonlight Role of PEDF in Breast Cancer

“…The co-administration with chemotherapy would lead to a less resistant population because TICs would have lost their stemness characteristics, as we discuss in the following paragraphs. The regulation of breast cancer progression through regulation of breast cancer stem cell-like properties has been recently described, probably mediated by the NF-κB cell signaling pathway [82,83], and the connection between chemoresistance, mesenchymal plasticity, and cancer stem cells in metastasis origin [84][85][86][87][88].…”

“…The anoikis effect is the apoptosis induced by lost, insufficient, or inappropriate interactions between the cell and the extracellular matrix [121,122]. Some of the cell-signaling pathways involved in cancer progression (such as BMPs) have also been related to proliferation, anoikis resistance, metastatic migration, and drug resistance of breast cancer cells [87,88,102,123]. This anoikis effect could be the basis for the interaction of TICs with the surrounding niche and could be involved in the loss of stemness properties and chemotherapy resistance [98].…”