It was recently proposed that
UDP-galactose:ceramide galactosyltransferase (UGT8),
enzyme responsible for synthesis of
galactosylceramide (GalCer), is a significant index of
tumor aggressiveness and a potential marker for the prognostic evaluation of lung
metastases in
breast cancer. To further reveal the role of UGT8 and GalCer in
breast cancer progression, tumorigenicity and metastatic potential of control MDA-MB-231 cells (MDA/LUC) and MDA-MB-231 cells (MDA/LUC-shUGT8) with highly decreased expression of UGT8 and GalCer after stable expression of
shRNA directed against UGT8
mRNA was studied in vivo in athymic nu/nu mice. Control MDA/LUC cells formed
tumors and metastatic colonies much more efficiently in comparison to MDA/LUC-shUGT8 cells with suppressed synthesis of GalCer after their, respectively, orthotopic and intracardiac
transplantation. These findings indicate that UGT8 and GalCer have a profound effect on tumorigenic and metastatic properties of
breast cancer cells. In accordance with this finding, immunohistochemical staining of
tumor specimens revealed that high expression of UGT8 accompanied by accumulation of GalCer in MDA-MB-231 cells is associated with a much higher proliferative index and a lower number of apoptotic cells in comparison to the MDA/LUC-shUGT8 cells. In addition, it was found that expression of UGT8 in MDA-MB-231 cells increased their resistance to apoptosis induced by
doxorubicin in vitro. Therefore, these data suggest that accumulation of GalCer in
tumor cells inhibits apoptosis, which would facilitates metastatic cells to survive in the hostile microenvironment of
tumor in target organ.