Carcinogenesis Advance Access originally published online on January 3, 2008
Carcinogenesis 2008 29(3):510-518; doi:10.1093/carcin/bgm280
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
The transglutaminase 2 gene (TGM2), a potential molecular marker for chemotherapeutic drug sensitivity, is epigenetically silenced in breast cancer
Department of Biochemistry and Molecular Biology and University of Florida Shands Cancer Center Program in Cancer Genetics, Epigenetics and Tumor Virology
1 Department of Pathology, Immunology and Laboratory Medicine, University of Florida College of Medicine, Box 100245, Gainesville, FL 32610, USA
* To whom correspondence should be addressed. Tel: 352 273 5458; Fax: 352 392 1445; Email: kdbrown1{at}ufl.edu
Tissue transglutaminase (TG2) is a ubiquitously expressed enzyme capable of catalyzing protein cross-links. TG2-dependent cross-links are important in extracellular matrix integrity and it has been proposed that this TG2 activity establishes a barrier to tumor spread. Furthermore, TG2 controls sensitivity to the chemotherapeutic drug doxorubicin. Both doxorubicin sensitivity and TG2 expression are highly variable in cultured human breast cancer cell lines and inspection of the human gene (termed TGM2) determined that a canonical CpG island exists within its 5' flank. These features, when combined with its potential tumor suppressor activity, make TG2 an attractive candidate for epigenetic silencing. Consistent with this, we observed that culturing breast tumor cells with the DNA demethylating agent 5-aza-2'-deoxycytidine (5-azadC) resulted in a robust increase in TG2 expression. Analysis of DNA harvested from cultured lines and primary breast tumor samples indicated that TGM2 often displays aberrant hypermethylation and that there is a statistically significant correlation between gene methylation and reduced expression. Finally, we observed that doxorubicin-resistant MCF-7/ADR cells do not show TGM2 silencing but that doxorubicin-sensitive MCF-7 cells do and that culturing MCF-7 cells on 5-azadC and subsequently restoring TG2 expression reduced sensitivity to doxorubicin. This work indicates that the TGM2 gene is a target for epigenetic silencing in breast cancer and suggests that this aberrant molecular event is a potential marker for chemotherapeutic drug sensitivity.
Abbreviations: 5-azadC, 5-aza-2'-deoxycytidine; BGS, bisulfite genomic sequencing; DCIS, ductal carcinoma in situ; ECM, extracellular matrix; gDNA, genomic DNA; IBC, invasive breast carcinoma; M, methylated; MSP, methylation-specific polymerase chain reaction; PCR, polymerase chain reaction; qPCR, quantitative polymerase chain reaction; RT–PCR, reverse transcription–polymerase chain reaction; TG2, type 2 transglutaminase
Received July 21, 2007; revised November 14, 2007; accepted December 1, 2007.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  S. E. Iismaa, B. M. Mearns, L. Lorand, and R. M. Graham Transglutaminases and Disease: Lessons From Genetically Engineered Mouse Models and Inherited Disorders Physiol Rev, July 1, 2009; 89(3): 991 - 1023. [Abstract] [Full Text] [PDF]
|
|