This research is a continuation of a string of studies on anti-estrogen resistance by Clarke, Cook, and their collaborators at Georgetown.
A paper published March 15 in Cancer Research, for example, described how a program known as the "unfolded protein response" or UPR, is activated in breast cells treated with the therapies once these cells sense stress. This response is activated when there is an accumulation of unfolded or misfolded proteins within the cell.
"Since cancers often grow rapidly, tumors may lack enough energy to properly fold proteins into the correct orientation. These misfolded proteins accumulate in the cell and trigger UPR," says Cook. "In normal cells, UPR is protective and if the stimuli lasts for an extended period of time UPR becomes pro-death. But we have found cancers use the UPR to promote survival."
In this study, the scientists zeroed in on GRP78 as the master regulator of UPR, thus promoting anti-estrogen resistance. It does this by preventing stressed cells to initiate programmed cell death, and by stimulating autophagy, which clears cells of the misfolded proteins while providing beneficial nutrition to the cell.
When the scientists inhibited GRP78 in anti-estrogen resistant cells, they promoted cell death and inhibited autophagy, resulting in increased numbers of dead cells.
They also found that GRP78 does not play a role in breast cancers that never responded to anti-estrogen therapy, indicating that initial resistance and acquired resistance represent separate biological phenomenon. "This observation is consistent with the emerging concept that acquired resistance may be an adaptive response," Cook says.
She also notes that elevated GRP78 has been found in different
|Contact: Karen Mallet|
Georgetown University Medical Center