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High frequency of hypermethylation at the 14-3-3 sigma locus leads to gene silencing in breast cancer.

Publication ,  Journal Article
Ferguson, AT; Evron, E; Umbricht, CB; Pandita, TK; Chan, TA; Hermeking, H; Marks, JR; Lambers, AR; Futreal, PA; Stampfer, MR; Sukumar, S
Published in: Proc Natl Acad Sci U S A
May 23, 2000

Expression of 14-3-3 final sigma (final sigma) is induced in response to DNA damage, and causes cells to arrest in G(2). By SAGE (serial analysis of gene expression) analysis, we identified final sigma as a gene whose expression is 7-fold lower in breast carcinoma cells than in normal breast epithelium. We verified this finding by Northern blot analysis. Remarkably, final sigma mRNA was undetectable in 45 of 48 primary breast carcinomas. Genetic alterations at final sigma such as loss of heterozygosity were rare (1/20 informative cases), and no mutations were detected (0/34). On the other hand, hypermethylation of CpG islands in the final sigma gene was detected in 91% (75/82) of breast tumors and was associated with lack of gene expression. Hypermethylation of final sigma is functionally important, because treatment of final sigma-non-expressing breast cancer cell lines with the drug 5-aza-2'-deoxycytidine resulted in demethylation of the gene and synthesis of final sigma mRNA. Breast cancer cells lacking final sigma expression showed increased number of chromosomal breaks and gaps when exposed to gamma-irradiation. Therefore, it is possible that loss of final sigma expression contributes to malignant transformation by impairing the G(2) cell cycle checkpoint function, thus allowing an accumulation of genetic defects. Hypermethylation and loss of final sigma expression are the most consistent molecular alterations in breast cancer identified so far.

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Published In

Proc Natl Acad Sci U S A

DOI

ISSN

0027-8424

Publication Date

May 23, 2000

Volume

97

Issue

11

Start / End Page

6049 / 6054

Location

United States

Related Subject Headings

  • Tyrosine 3-Monooxygenase
  • Tumor Cells, Cultured
  • Transfection
  • Transcription, Genetic
  • Recombinant Fusion Proteins
  • Radiation Tolerance
  • RNA, Neoplasm
  • RNA, Messenger
  • Proteins
  • Protein Biosynthesis
 

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Ferguson, A. T., Evron, E., Umbricht, C. B., Pandita, T. K., Chan, T. A., Hermeking, H., … Sukumar, S. (2000). High frequency of hypermethylation at the 14-3-3 sigma locus leads to gene silencing in breast cancer. Proc Natl Acad Sci U S A, 97(11), 6049–6054. https://doi.org/10.1073/pnas.100566997
Ferguson, A. T., E. Evron, C. B. Umbricht, T. K. Pandita, T. A. Chan, H. Hermeking, J. R. Marks, et al. “High frequency of hypermethylation at the 14-3-3 sigma locus leads to gene silencing in breast cancer.Proc Natl Acad Sci U S A 97, no. 11 (May 23, 2000): 6049–54. https://doi.org/10.1073/pnas.100566997.
Ferguson AT, Evron E, Umbricht CB, Pandita TK, Chan TA, Hermeking H, et al. High frequency of hypermethylation at the 14-3-3 sigma locus leads to gene silencing in breast cancer. Proc Natl Acad Sci U S A. 2000 May 23;97(11):6049–54.
Ferguson, A. T., et al. “High frequency of hypermethylation at the 14-3-3 sigma locus leads to gene silencing in breast cancer.Proc Natl Acad Sci U S A, vol. 97, no. 11, May 2000, pp. 6049–54. Pubmed, doi:10.1073/pnas.100566997.
Ferguson AT, Evron E, Umbricht CB, Pandita TK, Chan TA, Hermeking H, Marks JR, Lambers AR, Futreal PA, Stampfer MR, Sukumar S. High frequency of hypermethylation at the 14-3-3 sigma locus leads to gene silencing in breast cancer. Proc Natl Acad Sci U S A. 2000 May 23;97(11):6049–6054.
Journal cover image

Published In

Proc Natl Acad Sci U S A

DOI

ISSN

0027-8424

Publication Date

May 23, 2000

Volume

97

Issue

11

Start / End Page

6049 / 6054

Location

United States

Related Subject Headings

  • Tyrosine 3-Monooxygenase
  • Tumor Cells, Cultured
  • Transfection
  • Transcription, Genetic
  • Recombinant Fusion Proteins
  • Radiation Tolerance
  • RNA, Neoplasm
  • RNA, Messenger
  • Proteins
  • Protein Biosynthesis