Protein Linked to Development of Drug Resistance by Breast Cancer Cells

Cancer researchers have found that the protein glucose-regulated protein 78 (GRP78), which is activated in some types of breast tumor cells, may be a key factor in the development of resistance to the primary chemotherapeutic agents tamoxifen and fulvestrant.

Treatment of breast cancer with antiestrogen drugs is designed to induce apoptosis in the more than 70% of breast cancers that express estrogen receptors. However, in many cases, treatment is not effective or - after an initial positive response - the tumor becomes resistant to the drugs.

Investigators at Georgetown University (Washington DC, USA) examined the relationship between GRP78 activation and the development of anti-estrogen resistance by breast cancer cells.

They reported in the July 1, 2012, issue of the journal Cancer Research that tumors with acquired resistance to antiestrogen treatment overexpressed GRP78, while GRP78 overexpression was not observed in cases where the cancer cells were always resistant to the drugs. Knockdown of GRP78 restored antiestrogen sensitivity in resistant cells, and overexpression of GRP78 promoted resistance in sensitive cells.

At the molecular level, GRP78 integrated multiple cellular signaling pathways to inhibit apoptosis and stimulate prosurvival autophagy. GRP78 stimulation of autophagy enabled cancer cells to metabolize misfolded and potentially toxic proteins utilizing a mechanism known as the "unfolded protein response" or UPR.

"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," said first author Dr. Katherine Cook, an oncology researcher at Georgetown University. "In normal cells UPR is protective, and if the stimuli last for an extended period of time, UPR becomes pro-death. But we have found cancers use the UPR to promote survival. Since GRP78 plays such an important role in drug resistance, it would be of great benefit to develop agents that target this protein."

That GRP78 does not play a role in breast cancers that never responded to antiestrogen therapy suggests that initial resistance and acquired resistance represent separate biological pathways. "This observation is consistent with the emerging concept that acquired resistance may be an adaptive response," said Dr. Cook.

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