Transglutaminase 2 overexpression in tumor stroma identifies invasive ductal carcinomas of breast at high risk of recurrence.
BACKGROUND
Molecular markers for predicting breast cancer patients at high risk of recurrence are urgently needed for more effective disease management. The impact of alterations in extracellular matrix components on tumor aggressiveness is under intense investigation. Overexpression of Transglutaminase 2 (TG2), a multifunctional enzyme, in cancer cells impacts epithelial mesenchymal transition, growth, invasion and interactions with tumor microenvironment. The objective of our study is to determine the clinical relevance of stromal TG2 overexpression and explore its potential to identify breast cancers at high risk of recurrence.


METHODS
This retrospective study is based on immunohistochemical analysis of TG2 expression in normal breast tissues (n = 40) and breast cancers (n = 253) with clinical, pathological and follow-up data available for up to 12 years. TG2 expression was correlated with clinical and pathological parameters as well as disease free survival (DFS) of breast cancer patients.


RESULTS
Stromal TG2 overexpression was observed in 114/253 (45.0%) breast cancer tissues as compared to breast normal tissues. Among invasive ductal carcinomas (IDC) of the breast, 97/168 (57.7%) showed strong TG2 expression in tumor stroma. Importantly, IDC patients showing stromal TG2 accumulation had significantly reduced DFS (mean DFS = 110 months) in comparison with patients showing low expression (mean DFS = 130 months) in Kaplan-Meier survival analysis (p<0.001). In Cox multivariate regression analysis, stromal TG2 accumulation was an independent risk factor for recurrence (p = 0.006, Hazard's ratio, H.R. = 3.79). Notably, these breast cancer patients also showed immunostaining of N-epsilon gamma-glutamyl lysine amino residues in tumor stroma demonstrating the transamidating activity of TG2.


CONCLUSIONS
Accumulation of TG2 in tumor stroma is an independent risk factor for identifying breast cancer patients at high risk of recurrence. TG2 overexpression in tumor stroma may serve as a predictor of poor prognosis for IDC of the breast.
Alex and Simona Shnaider Laboratory in Molecular Oncology, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Joseph and Wolf Lebovic Health Complex, Toronto, Ontario, Canada.
Jasmeet
J
Assi
Gunjan
G
Srivastava
Ajay
A
Matta
Martin C
MC
Chang
Paul G
PG
Walfish
Ranju
R
Ralhan
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000378:metabolism; D001943:Breast Neoplasms / Q000201:enzymology* / Q000473:pathology*; D018270:Carcinoma, Ductal, Breast / Q000201:enzymology* / Q000473:pathology*; D003593:Cytoplasm / Q000201:enzymology / Q000473:pathology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D051416:Focal Adhesion Protein-Tyrosine Kinases; D019204:GTP-Binding Proteins; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009364:Neoplasm Recurrence, Local / Q000201:enzymology* / Q000473:pathology*; D010766:Phosphorylation; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D012307:Risk Factors; D017154:Stromal Cells / Q000201:enzymology / Q000473:pathology; D011503:Transglutaminases / Q000378:metabolism*
D014408:Biomarkers, Tumor; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D051416:Focal Adhesion Protein-Tyrosine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D019204:GTP-Binding Proteins