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Simple Summary  In the present study, we define the expression of 15 selected circular RNAs, using a panel of 18 breast cancer cell lines recapitulating the heterogeneity of tumors and consisting of three distinct groups according to the mesenchymal/epithelial phenotype. We identify  circDOCK1-1  generated from the  DOCK1  gene as an important regulator of the epithelial differentiation of mammary tumour cells. In addition, our high-throughput transcriptomic studies provide information on the genes that are regulated by  circDOCK1-1 , casting new light on the gene networks involved in the processes underlying the development of mammary tumours. Our results further indicate that  circDOCK1-1  controls cell–cell adhesion and consequently random as well as directional motility. Besides their interest from a basic point of view, the data generated may be of translational relevance, as they suggest that strategies aimed at increasing the amounts or at stimulating the activity of  circDOCK1-1  may be of significance for the treatment of a subset of triple-negative breast cancer patients.    Abstract  Circular RNAs are regulatory molecules involved in numerous cellular processes and may be involved in tumour growth and diffusion. Here, we define the expression of 15 selected circular RNAs, which may control the process of epithelial-to-mesenchymal transition, using a panel of 18 breast cancer cell lines recapitulating the heterogeneity of these tumours and consisting of three groups according to the mesenchymal/epithelial phenotype. A circular RNA from the  DOCK1  gene ( hsa_circ_0020397 ) shows low/undetectable levels in triple-negative mesenchymal cell lines, while its content is high in epithelial cell lines, independent of estrogen receptor or HER2 positivity. RNA-sequencing experiments performed on the triple-negative/mesenchymal  MDA-MB-231  and  MDA-MB-157  cell lines engineered to overexpress  hsa_circ_0020397  demonstrate that the circRNA influences the expression of 110 common genes. Pathway analysis of these genes indicates that overexpression of the circular RNA differentiates the two mesenchymal cell lines along the epithelial pathway and increases cell-to-cell adhesion. This is accompanied by growth inhibition and a reduction in the random/directional motility of the cell lines. The upregulated  AGR2 ,  ENPP1 , and  PPP1R9A  genes as well as the downregulated  APOE ,  AQP3 ,  CD99L2 , and  IGFBP4  genes show an opposite regulation by  hsa_circ_0020397  silencing in luminal  CAMA1  cells. The results provide novel insights into the role played by specific circular RNAs in the generation/progression of breast cancer.

cancers

A DOCK1 Gene-Derived Circular RNA Is Highly Expressed in Luminal Mammary Tumours and Is Involved in the Epithelial Differentiation, Growth, and Motility of Breast Cancer Cells