Trop-2 stimulates the growth of human cancer cells through fusion to Cyclin D1

The TROP2 gene encodes a transmembrane calcium signal transducer, that stimulates the growth of human cancers. The widespread overexpression of Trop-2 and of its growth stimulatory activity suggested the existence of an underlying common, conserved signal-transduction module, driven by Trop-2 in expressing cells. We investigated the Trop-2 signaling network in tumor cells and discovered a fusion transcript between TROP2 and CYCLIN D1. This transforms naïve, primary cells in vitro and induces aggressive tumor growth in vivo in cooperation with activated RAS. Silencing of the chimeric mRNA inhibits the growth of breast cancer cells. The CYCLIN D1-TROP2 mRNA was expressed by a large fraction of the human gastro-intestinal, ovarian and endometrial tumors analysed. It was most frequently detected in intestinal cell, aneuploid cancers, and it is coexpressed with activated RAS oncogenes, consistent with a cooperative transforming activity in human cancers. The chimeric mRNA is a bicistronic transcript of post-transcriptional origin, that independently translates the Cyclin D1 and Trop-2 proteins. This leads to a higher CYCLIN D1 mRNA stability, with inappropriate expression during the cell cycle. The stabilized CYCLIN D1 mRNA cooperates with TROP2 in stimulating the growth of the expressing cells. These findings demonstrate a novel epigenetic, oncogenic mechanism, which appears to be widespread in human cancers. This opens novel avenue for anti-cancer therapies and diagnosis, and reveals a novel mechanism of regulation of gene expression.