title: A synonymous polymorphism of the Tristetraprolin (TTP) gene, an AU-rich mRNA-binding protein, affects translation efficiency and response to Herceptin treatment in breast cancer patients.
abstract: Post-transcriptional regulation plays a central role in cell differentiation and proliferation. Among the regulatory factors involved in this mechanism, Tristetraprolin (ZFP36 or TTP) is the prototype of a family of RNA-binding proteins that bind to adenylate and uridylate (AU)-rich sequences in the 3'UTR of mRNAs, which promotes their physiological decay. Here, we investigated whether TTP correlates with tumor aggressiveness in breast cancer and is a novel prognostic factor for this neoplasia. By immunoblot analysis, we determined the amount of TTP protein in different breast cancer cell lines and found an inverse correlation between aggressiveness and metastatic potential. TTP mRNA levels were very variable among cells lines and did not correlate with protein levels. Interestingly, by sequencing the entire TTP coding region in Hs578T cells that do not express the TTP protein, we identified a synonymous polymorphism (rs3746083) that showed a statistically significant association with a lack of response to Herceptin/Trastuzumab in HER2-positive-breast cancer patients. Even though this genetic change did not modify the corresponding amino acid, we performed functional studies and showed an effect on protein translation associated with the variant allele with respect to the wild-type. These data underline the importance of synonymous variants on gene expression and the potential role of TTP genetic polymorphisms as a prognostic marker for breast cancer.
authors.affiliation: University Nice-Sophia Antipolis Institute of Developmental Biology and Cancer, CNRS UMR 6543, France.
authors.forename: Paola
authors.initials: P
authors.lastname: Griseri
authors.forename: Christine
authors.initials: C
authors.lastname: Bourcier
authors.forename: Corinne
authors.initials: C
authors.lastname: Hieblot
authors.forename: Khadija
authors.initials: K
authors.lastname: Essafi-Benkhadir
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Chamorey
authors.forename: Christian
authors.initials: C
authors.lastname: Touriol
authors.forename: Gilles
authors.initials: G
authors.lastname: Pagès
mesh_terms: D043925:Angiogenesis Inducing Agents / Q000378:metabolism; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology / Q000627:therapeutic use*; D001483:Base Sequence; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002999:Clone Cells; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism; D050505:Mutant Proteins / Q000378:metabolism; D009361:Neoplasm Invasiveness; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D014176:Protein Biosynthesis / Q000187:drug effects / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D014162:Transfection; D000068878:Trastuzumab; D051816:Tristetraprolin / Q000235:genetics* / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: D043925:Angiogenesis Inducing Agents; D061067:Antibodies, Monoclonal, Humanized; D016209:Interleukin-8; D050505:Mutant Proteins; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D051816:Tristetraprolin; D042461:Vascular Endothelial Growth Factor A; C497552:ZFP36 protein, human; D000068878:Trastuzumab