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.
| Original language | English |
|---|---|
| Article number | ddr390 |
| Pages (from-to) | 4556-4568 |
| Number of pages | 13 |
| Journal | Human Molecular Genetics |
| Volume | 20 |
| Issue number | 23 |
| DOIs | |
| Publication status | Published - Dec 2011 |
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ASJC Scopus subject areas
- Genetics
- Genetics(clinical)
- Molecular Biology
Cite this
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. / Griseri, Paola; Bourcier, Christine; Hieblot, Corinne; Essafi-Benkhadir, Khadija; Chamorey, Emmanuel; Touriol, Christian; Pag̀s, Gilles.
In: Human Molecular Genetics, Vol. 20, No. 23, ddr390, 12.2011, p. 4556-4568.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - 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
AU - Griseri, Paola
AU - Bourcier, Christine
AU - Hieblot, Corinne
AU - Essafi-Benkhadir, Khadija
AU - Chamorey, Emmanuel
AU - Touriol, Christian
AU - Pag̀s, Gilles
PY - 2011/12
Y1 - 2011/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=81255147990&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=81255147990&partnerID=8YFLogxK
U2 - 10.1093/hmg/ddr390
DO - 10.1093/hmg/ddr390
M3 - Article
C2 - 21875902
AN - SCOPUS:81255147990
VL - 20
SP - 4556
EP - 4568
JO - Human Molecular Genetics
JF - Human Molecular Genetics
SN - 0964-6906
IS - 23
M1 - ddr390
ER -