Orlando, Fla. − Most breast cancers are fueled by estrogen, and anti-estrogenic agents often work for a time to control the cancers. But many of these cancers become resistant to the drugs for reasons that are not understood, leaving patients with limited treatment options.
Now researchers at the Georgetown Lombardi Comprehensive Cancer Center, a part of Georgetown University Medical Center (GUMC), say that this resistance appears to be due to a natural stress response in cells, and that the biochemical molecules involved in this response might prove to be a new drug target. They reported their findings at the American Association for Cancer Research (AACR) 102nd Annual Meeting 2011.
They found that breast cancer cells protect themselves against two anti-estrogen drugs (Tamoxifen and Faslodex) by hijacking and switching on a biological process inside the cells that is normally used when proteins are produced that don’t have the right shape.
It had not been known, before this study, that this program - the “unfolded protein response” or UPR - could be triggered when breast cancer cells are “attacked” by anti-estrogen drugs, says the study’s lead investigator, Ayesha Shajahan, Ph.D., an oncology research instructor and researcher in the laboratory of Robert Clarke, Ph.D., D.Sc., Dean for Research at GUMC and professor of oncology at Georgetown Lombardi. Clarke will be presenting the results at AACR.
If a UPR is activated, a cell can do one of two things, Shajahan says: it can turn on a pro-survival pathway or it can turn on a process that ultimately destroys the cell. The cells they studied all chose to “man the forts” to survive. They hunker down and wait out the attack, a tactic that allows the cell to resist anti-cancer treatment.
“We found that anti-estrogen resistant cancer cells are much more likely to turn on the pro-survival pathway than are cells that are sensitive to estrogen,” says Shajahan.
They also found that anti-estrogen resistant breast cancer cells over-express the X-Box Binding Protein (XBP1), which turns on UPR signaling, and that specific resistance to Faslodex (Fulvestrant) occurs because of increased levels of over-expression of a XBP1 subtype, XBP1(s).
The study was funded by the Department of Defense Idea Award BC073977 to Clarke. The authors report having no personal financial interests related to the study.
About Georgetown Lombardi Comprehensive Cancer Center
The Georgetown Lombardi Comprehensive Cancer Center, part of Georgetown University Medical Center and Georgetown University Hospital, seeks to improve the diagnosis, treatment, and prevention of cancer through innovative basic and clinical research, patient care, community education and outreach, and the training of cancer specialists of the future. Lombardi is one of only 41 comprehensive cancer centers in the nation, as designated by the National Cancer Institute, and the only one in the Washington, DC, area. For more information, go to http://lombardi.georgetown.edu.
About Georgetown University Medical Center
Georgetown University Medical Center is an internationally recognized academic medical center with a three-part mission of research, teaching and patient care (through MedStar Health). GUMC’s mission is carried out with a strong emphasis on public service and a dedication to the Catholic, Jesuit principle of cura personalis -- or "care of the whole person." The Medical Center includes the School of Medicine and the School of Nursing & Health Studies, both nationally ranked; Georgetown Lombardi Comprehensive Cancer Center, designated as a comprehensive cancer center by the National Cancer Institute; and the Biomedical Graduate Research Organization (BGRO), which accounts for the majority of externally funded research at GUMC including a Clinical Translation and Science Award from the National Institutes of Health. In fiscal year 2009-2010, GUMC accounted for nearly 80 percent of Georgetown University's extramural research funding.