Prognostic significance of tissue transglutaminase in drug resistant and metastatic breast cancer.
OBJECTIVE
Drug resistance and metastasis pose major impediments in the successful treatment of cancer. We previously reported that multidrug-resistant breast cancer cells exhibit high levels of tissue transglutaminase (TG2; EC 2.3.2.13). Because the drug-resistant and metastatic phenotypes are thought to share some common pathways, we sought to determine whether metastatic breast cancer cells express high levels of TG2.


METHODS
The metastatic breast cancer cell line MDA-MB-231 and the sublines derived from it were tested for TG2 expression. Similarly, several sublines derived from an immortal but normal breast epithelial cell line, MCF10A, representing various stages in breast cancer progression were studied for TG2 expression. The primary and nodal tumor samples from 30 patients with breast cancer were also studied for TG2 expression.


RESULTS
The MDA-MB-231 cells expressed high basal levels of TG2. Two clones derived from this cell line, MDA231/cl.9 and MDA231/cl.16, showed a 10- to 15-fold difference in TG2 level. TG2-deficient MDA231/cl.9 cells exhibited higher sensitivity to doxorubicin and were less invasive than were the TG2-sufficient MDA231/cl.16 cells. The MCF10A-derived sublines had increased TG2 expression as they advanced from noninvasive to an invasive phenotype. Importantly, the metastatic lymph node tumors from patients with breast cancer showed significant higher levels of TG2 expression compared with the primary tumors from the same patients.


CONCLUSIONS
TG2 expression is up-regulated in drug-resistant and metastatic breast cancer cells, and it can serve as a valuable prognostic marker for these phenotypes.
Mehta
Kapil
K
Department of Experimental Therapeutics-Unit 422, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA. kmehta@mdanderson.org
Fok
Jansina
J
Miller
Fred R
FR
Koul
Dimpy
D
Sahin
Aysegul A
AA
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects; D014408:Biomarkers, Tumor; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000556:secondary; D002465:Cell Movement; D002470:Cell Survival / Q000187:drug effects; D003094:Collagen / Q000378:metabolism; D018450:Disease Progression; D004317:Doxorubicin / Q000009:adverse effects; D004338:Drug Combinations; D019008:Drug Resistance, Neoplasm; D005260:Female; D019204:GTP-Binding Proteins / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007797:Laminin / Q000378:metabolism; D008207:Lymphatic Metastasis; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011509:Proteoglycans / Q000378:metabolism; D011503:Transglutaminases / Q000378:metabolism*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
D000903:Antibiotics, Antineoplastic; D014408:Biomarkers, Tumor; D004338:Drug Combinations; D007797:Laminin; D011509:Proteoglycans; C059485:matrigel; D004317:Doxorubicin; D003094:Collagen; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins