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Scientists identify protein involved in restoring effectiveness of common treatment for breast cancer

Breast cancer is the most frequently diagnosed cancer among women, with estrogen-receptor-positive (ER+) being the most common type. Drugs used to treat this cancer, such as tamoxifen and Faslodex, block the hormone estrogen receptor that ER+ cancer cells need to grow. One problem with these treatments is that many tumors initially responsive to the drugs develop resistance, making the medicines less effective.   

However, scientists at Wake Forest Baptist Medical Center have succeeded in enhancing and restoring sensitivity to an estrogen-blocking drug in ER+ tumors in an animal model. The research findings are published in the Oct. 1 issue of the journal Cancer Research.

Previous research showed that glucose-regulated protein 78 (GRP78) is elevated in breast cancer tumors and that targeting it could enhance and restore sensitivity in estrogen targeted therapy-resistant cells in vitro.

In this study, the researchers sought to determine if they could target GRP78 in breast cancer tumors in an animal model.

They first tested a GRP78-targeting molecule called a morpholino, which can modify gene expression. The morpholino successfully inhibited GRP78 and restored sensitivity to tamoxifen in the resistant tumors.

“Morpholinos are candidate drugs already being used to target other proteins in clinical trials to treat prostate cancer but this is the first time inhibiting the gene expression of GRP78 with these agents may have potential to overcome resistance to chemotherapy,” said Katherine Cook, Ph.D., assistant professor at Wake Forest School of Medicine, a part of Wake Forest Baptist, and the study’s lead author.

In addition, metabolic analysis of breast cancer cells showed that suppressing GRP78 increased the intracellular concentrations of essential polyunsaturated fats, including linoleic acid. These data suggest a novel role of GRP78 in mediating cellular lipid metabolism.

To validate the effect of GRP78-regulated metabolic changes, the scientists treated the same tumor-bearing mice with different doses of linoleic acid and found that this approach had the same effect as targeting GRP78 in restoring tamoxifen sensitivity to the tumors.

This study highlights the importance of fatty acid regulation in cancer, Cook said. “While drugs against GRP78 protein are further along as a potential cancer therapy, dietary measures such as polyunsaturated fatty acid supplementation may also enhance therapeutic sensitivity.”

Cook and her team are currently looking at dietary effects on breast cancer in an animal model using different types of fatty acids and diets to see whether they can effect tumor growth and/or endocrine therapy responsiveness.

Co-authors are: David R. Soto-Pantoja, Ph.D., of Wake Forest Baptist; Pamela A.G. Clarke, M. Idalia Cruz, Alan Zwart, Anni Warri, Ph.D., Leena Hilakiva-Clarke, Ph.D., and Robert Clarke, Ph.D., D.Sc., of Georgetown University Medical Center; and David D. Roberts, Ph.D., of the National Institutes of Health.

Support for the research was provided by a Department of Defense Breast Cancer Research Program Postdoctoral Fellowship, BC112023 (Cook); the National Cancer Institute Career Transition Award, 1K22CA181274-01A1 (Soto-Pantoja); U.S. Department of Health and Human Services, R01-CA131465, U01-CA184902 and U54-CA149147 (Robert Clarke); and the Intramural Research Program of the National Institutes of Health (Roberts). 

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