Inhibiting single protein could help restore sensitivity to common treatment for breast cancer

A team of investigators led by researchers at Georgetown Lombardi Comprehensive Cancer Center has found, in animal models of human breast cancer, that inhibiting a single protein restores sensitivity to tamoxifen, a commonly used drug for treatment of some breast cancers.

Researchers say the findings, reported in the journal Cancer Research, also show that targeting the protein, glucose-regulated protein 78 (GRP78), toxically stresses breast cancer cells, and so could be an effective therapeutic option for all forms of endocrine-resistant breast cancer, and, possibly, other cancer subtypes.

"We believe that the strategy of silencing GRP78 would work with all other endocrine therapies used in the clinic, and may work in other types of breast cancer and other cancers," says the study's senior investigator, Robert Clarke, PhD, DSc, professor of oncology and Dean for Research at Georgetown University Medical Center.

"We found that silencing GRP78 does not allow breast cancer cells to effectively use their mitochondria — their power plants — and that alone can lead to cell death. However, adding tamoxifen to a GRP78 inhibitor offers an ultra effective, lethal double whammy to the most common form of breast cancer," Clarke says.

He adds that this study potentially offers "a very promising advance" in breast cancer research to understand resistant cancer. About 70 percent of all breast cancers are estrogen-receptor positive (ER+), which means they depend on estrogen to grow. In many of these cancers, treatment involves preventing estrogen from reaching the cancer cell. However, about 50 percent of treated tumors develop resistance to hormone blocking treatments.

GRP78 inhibitors have already been developed and are being tested in preclinical studies for other conditions, but for this research, Georgetown investigators created their own GRP78 inhibitor.

The Georgetown researchers have long been studying the role of GRP78 in ER+ breast cancer. In 2012, they reported, for the first time, that GRP78 is a regulates resistance to tamoxifen as well as fulvestrant, another endocrine therapy, and that it can control the death of breast cancer cells in the laboratory.

In this study, they investigated cellular mechanisms of GRP78 in a living model of breast cancer — mice implanted with human ER+ breast tumors.

Investigators found that GRP78 plays another crucial role — that of regulating the cell's metabolism of lipids (fats). As GRP78 levels increase, mitochondria in the cancer cell escalate their burning of fats to provide energy and new growth, says the study's lead researcher, Katherine Loree Cook, PhD, who was a postdoctoral fellow in Clarke's lab at the time of the study and is now an assistant professor at Wake Forest University.

But when their drug inhibited GRP78 protein production, the level of polyunsaturated fatty acids (PUFAs) increased inside cancer cells because the fat was not being burned inside mitochondria.

A build-up of PUFAs inside the cells produces an immune response targeting the cancer cells for destruction.

"So not only is GRP78 inhibition reducing the ability of a cell to produce energy, it is flagging recruitment of immune cells whose job is to chew up the cancer cell," says Cook.

Finally, the team observed that using a GRP78 inhibitor and tamoxifen "enhances the effectiveness of tamoxifen in tumors that were already sensitive to the drug," Cook says.

Clarke say this same response might be possible with drugs that treat breast cancers not powered by estrogen — as well as other tumor types. "Studies have found that GRP78 overexpression promotes resistance to several cancer chemotherapies, used for breast cancer and other tumors. Therefore, GRP78 inhibition may be beneficial for the treatment of other types of chemotherapeutic resistant tumors," Clarke says.

He adds that the research team is studying the approach in other animal models before moving into human studies.