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

¹ Unit of Cancer Pathology, Department of Oncology and Neurosciences and CeSI, University "G. d' Annunzio" Foundation, Chieti Scalo, Italy; ² Laboratory of Experimental Oncology, Department of Cell Biology and Oncology; and ³ Animal Care Unit and Experimental Models, Institute Mario Negri Sud, Santa Maria Imbaro, Chieti, Italy

Requests for reprints: Saverio Alberti, Unit of Cancer Pathology, Center for Excellence in Research on Aging, University "G. d' Annunzio" Foundation, Via Colle dell' Ara, 66100 Chieti Scalo (Chieti), Italy. Phone/Fax: 39-0871-541-551; E-mail: s.alberti{at}unich.it.

Key Words: human tumors • oncogenes • cell growth • mRNA processing

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. [Cancer Res 2008;68(19):8113–21]

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