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
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
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).