MALAT1-dependent hsa_circ_0076611 regulates translation rate in triple-negative breast cancer

Vascular Endothelial Growth Factor A (VEGFA) is the most commonly expressed angiogenic growth factor in solid tumors and is generated as multiple isoforms through alternative mRNA splicing. Here, we show that lncRNA <em>MALAT1</em> (metastasis-associated lung adenocarcinoma transcript 1) and ID4 (inhibitor of DNA-binding 4) protein, previously referred to as regulators of linear isoforms of <em>VEGFA</em>, induce back-splicing of <em>VEGFA</em> exon 7, producing circular RNA circ_0076611. Circ_0076611 is detectable in triple-negative breast cancer (TNBC) cells and tissues, in exosomes released from TNBC cells and in the serum of breast cancer patients. Circ_0076611 interacts with a variety of proliferation-related transcripts, included <em>MYC</em> and <em>VEGFA</em> mRNAs, and increases cell proliferation and migration of TNBC cells. Mechanistically, circ_0076611 favors the expression of its target mRNAs by facilitating their interaction with components of the translation initiation machinery. These results add further complexity to the multiple <em>VEGFA</em> isoforms expressed in cancer cells and highlight the relevance of post-transcriptional regulation of <em>VEGFA</em> expression in TNBC cells.