Regulation of HER-2 oncogene expression by cyclooxygenase-2 and prostaglandin E2.
The oncoprotein HER-2/neu is a prosurvival factor and its overexpression has been correlated with adverse prognosis in breast cancers. High levels of the cyclooxygenase-2 (COX-2), a proinflammatory and antiapoptotic enzyme, were detected in HER-2-positive tumors and this observation was linked to an HER-2-mediated induction of COX-2 gene transcription. Here, we report that COX-2 expression, and synthesis of its major enzymatic product, PGE2, leads in turn to an enhanced HER-2 expression. Moreover, COX-2 enzymatic inhibition dramatically reduced HER-2 protein levels, efficiently increased the cancer cells sensitility to chemotherapeutic treatment and acted in synergy with HER-2 inhibitor, trastuzumab. Therefore, we propose an original model where HER-2 and COX-2 transcriptionally regulate each other in a positive loop.
Benoit
Valérie
V
Laboratory of Medical Chemistry and Human Genetics, Center for Molecular and Cellular Therapy, University of Liège, Belgium.
Relic
Biserka
B
Leval Xd
Xavier de
Xd
Chariot
Alain
A
Merville
Marie-Paule
MP
Bours
Vincent
V
D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000096:biosynthesis*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D018734:Genes, erbB-2; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism*; D008565:Membrane Proteins; D008957:Models, Genetic; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
D051546:Cyclooxygenase 2; D015232:Dinoprostone; D007527:Isoenzymes; D008565:Membrane Proteins; D011451:Prostaglandin-Endoperoxide Synthases; D012333:RNA, Messenger; D018719:Erb-b2 Receptor Tyrosine Kinases; C496540:PTGS2 protein, human