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

Paola Griseri, Christine Bourcier, Corinne Hieblot, Khadija Essafi-Benkhadir, Emmanuel Chamorey, Christian Touriol, Gilles Pag̀s

Research output: Contribution to journalArticle

51 Citations (Scopus)

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 languageEnglish
Article numberddr390
Pages (from-to)4556-4568
Number of pages13
JournalHuman Molecular Genetics
Volume20
Issue number23
DOIs
Publication statusPublished - Dec 2011

Fingerprint

Tristetraprolin
Protein Biosynthesis
Carrier Proteins
Breast Neoplasms
Messenger RNA
Genes
Therapeutics
Cell Line
RNA-Binding Proteins
Trastuzumab
3' Untranslated Regions
Genetic Polymorphisms
Cell Differentiation
Neoplasms
Alleles
Cell Proliferation

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 journalArticle

Griseri, Paola ; Bourcier, Christine ; Hieblot, Corinne ; Essafi-Benkhadir, Khadija ; Chamorey, Emmanuel ; Touriol, Christian ; Pag̀s, Gilles. / 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. In: Human Molecular Genetics. 2011 ; Vol. 20, No. 23. pp. 4556-4568.
@article{45ac2baa3d544907aae9565ebd1398a6,
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.",
author = "Paola Griseri and Christine Bourcier and Corinne Hieblot and Khadija Essafi-Benkhadir and Emmanuel Chamorey and Christian Touriol and Gilles Pag̀s",
year = "2011",
month = "12",
doi = "10.1093/hmg/ddr390",
language = "English",
volume = "20",
pages = "4556--4568",
journal = "Human Molecular Genetics",
issn = "0964-6906",
publisher = "Oxford University Press",
number = "23",

}

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 -