Novel role of BRCA1 in Metastasis - Amoeboid cell motility

The Breast Cancer 1 protein (BRCA1) is a tumor suppressor essential for cellular functions necessary for genome integrity. BRCA1 pathological mutation gene carriers develop metastatic TNBC disease. The motility plasticity of tumor cells is mediated by epithelial-to-mesenchymal (EMT) and mesenchymal-to-amoeboid (MAT) transitions, displaying specific characteristics in cell-cell junctions, actin cytoskeleton, matrix adhesion, and protease activity. This plasticity in motility patterns enables cancer cells to disseminate further and thus limits the efficiency of anti-metastasis therapies. Several papers indicate that BRCA1 is involved in metastasis.

Here, we show that reducing the expression levels of BRCA1 in TNBC human cell lines such as MDA-MB-231 using CRISPR\Cas9 alters cell morpho-kinetic characterization. Single Cell morphokinetic analysis demonstrates that the Knockout clones show an alteration of motility and morphological patterns compared to the control acquiring amoeboid cell motility characteristics. Immunofluorescence analysis demonstrated alteration of essential cytoskeletal protein levels and pattern of expression that are in agreement with the ameboid morphokinetic alteration. In parallel to BRCA1 knockout, MET mRNA levels and response to HGF/SF were altered. To our results show that BRCA1 knockout induces extensive MAT in MDA231 cells, and its absence directly promotes amoeboid cell motility, metastasis, an increase in invasiveness and disruption in the cell cycle. The new findings provide insights into the underlying mechanisms of BRCA1 and metastases formation, paving the way to increase the clinical benefit of the existing therapies.