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Last updated on April 24, 2014 at 14:09 EDT

Protein Blocks Anti-Estrogen Drugs?

July 2, 2012

(Ivanhoe Newswire) — Researchers have discovered a single molecule that they say is a major cause of resistance to anti-estrogen therapy used to prevent or treat breast cancer in high-risk women.

The researchers say glucose-regulated protein 78 (GRP78), which is triggered as breast cells become stressed from the agents tamoxifen and fulvestrant, turns off apoptosis (a cell death response) and turns on autophagy. Autophagy occurs when the cell “eats” and digests components within the cell body that the drugs have harmed, therefore providing nutrients needed to sustain life.

The research findings suggest that a new agent that inhibits GRP78 might provide a solution for the tens of thousands of women who develop resistance to anti-estrogen drugs. Though more than 70-percent of breast cancers express estrogen receptors that fuel cancer growth, about one-third of these cases fail to be cured by therapies that target this receptor.

“Since GRP78 plays such an important role in drug resistance, it would be of great benefit to develop agents that target this protein,” the study’s lead author, Katherine Cook, Ph.D., a postdoctoral investigator in the lab of Robert Clarke, Ph.D., D.Sc., senior study author and professor of oncology and Dean for Research at Georgetown University Medical Center, was quoted as saying.

Several GRP78 inhibitors have already been developed are currently being tested, but not yet at the level of human clinical trials. This is the first study to show that GRP78 is a regulator of resistance to tamoxifen and fulvestrant, as well as the first to reveal how GRP78 directly controls autophagy.

It has previously been unknown why estrogen-receptor positive breast tumors fail to respond, or initially respond and grow upon achieving resistance to these agents. These findings could have high translational impact and bring a new perspective to the molecular crosstalk between cell stress, apoptosis, and autophagy.

This research is a continuation of a string of studies about anti-estrogen resistance by Clarke, Cook, and their Georgetown collaborators. For example, a paper published March 15 in Cancer Research described how a program known as the “unfolded protein response” (UPR) is activated in breast cells treated with the therapies once these cells sense stress. An accumulation of unfolded or misfolded proteins inside the cell activate the response.

“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,” Cook was quoted as saying. “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 targeted GRP78 as the master regulator of UPR, therefore promoting anti-estrogen resistance. It does this by preventing stressed cells from initiating 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 larger amounts of dead cells.

Additionally, they found that GRP78 does not play a role in breast cancers that never responded to anti-estrogen therapy; this shows 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 was quoted as saying.

Elevated GRP78 has been found in different cancer types, including breast cancer, and in resistance to several different chemotherapy treatments.

Cook was quoted as saying, “The basic principle we establish of using GRP78 to integrate the cellular functions of apoptosis and autophagy raises the provocative question that this signaling may be widely applicable and represent a major stress response.”

Source: Cancer Research, July 2012