A Bicistronic CYCLIN D1-TROP2 mRNA Chimera Demonstrates a Novel Oncogenic Mechanism in Human Cancer

• Published in: Cancer research (Chicago, Ill.) Ill.), 2008-10, Vol.68 (19), p.8113-8121
• Main Authors: GUERRA, Emanuela, TREROTOLA, Marco, VACCA, Giovanna, LATTANZIO, Rossano, PIANTELLI, Mauro, ALBERTI, Saverio, DELL' ARCIPRETE, Roberta, BONASERA, Veronica, PALOMBO, Barbara, EL-SEWEDY, Tarek, CICCIMARRA, Tommaso, CRESCENZI, Carlo, LORENZINI, Franco, ROSSI, Cosmo
• Format: Article
• Language: English
• Subjects: Animals; Antigens, Neoplasm - genetics; Antigens, Neoplasm - physiology; Biological and medical sciences; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Carcinogenesis, carcinogens and anticarcinogens; Cell Adhesion Molecules - genetics; Cell Adhesion Molecules - physiology; Cell Transformation, Neoplastic - genetics; Cercopithecus aethiops; COS Cells; Female; General aspects; Genes, bcl-1 - physiology; Humans; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Nude; Oncogene Proteins, Fusion - genetics; Oncogene Proteins, Fusion - metabolism; Oncogene Proteins, Fusion - physiology; Ovarian Neoplasms - genetics; Ovarian Neoplasms - metabolism; Ovarian Neoplasms - pathology; Protein Biosynthesis - physiology; Rats; Rats, Sprague-Dawley; RNA, Messenger - genetics; RNA, Messenger - metabolism; Transplantation, Heterologous; Tumor Cells, Cultured; Tumors
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-07-6135

A chimeric CYCLIN D1-TROP2 mRNA was isolated from human ovarian and mammary cancer cells. The CYCLIN D1-TROP2 mRNA was shown to be a potent oncogene as it 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 gastrointestinal, ovarian, and endometrial tumors analyzed. It is 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 is a novel mechanism of CYCLIN D1 activation that achieves the truncation of the CYCLIN D1 mRNA in the absence of chromosomal rearrangements. 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 show a novel epigenetic, oncogenic mechanism, which seems to be widespread in human cancers.