An essential protein for normal stem cell renewal also promotes the growth of breast cancer stem cells when it's overproduced in those cells, researchers at The University of Texas MD Anderson Cancer Center report in the February edition of Cancer Cell.
In mouse and lab experiments, the team also discovered that two drugs block the cascade of molecular events that they describe in the paper, thwarting formation of breast tumor-initiating cells.
"Overexpression of the EZH2 protein has been linked to breast cancer progression, but the molecular details of that connection were unknown," said senior author Mien-Chie Hung, Ph.D., professor and chair of MD Anderson's Department of Molecular and Cellular Oncology.
"Tumor-initiating cancer cells that arise from the primary cancer stem cells also are thought to drive cancer progression," Hung said. "This research connects EZH2 to the growth of breast tumor-initiating cells."
EZH2 blocks DNA damage repair
The molecular chain of events that improves self-renewal, survival and growth of these breast cancer stem cells can be initiated by oxygen-starved portions of a tumor, Hung said. This hypoxia stimulates a protein that in turn causes overexpression of EZH2.
Abundant EZH2, the team showed, dampens production of an important protein involved in DNA damage repair. Unrepaired chromosomal damage then amplifies production of RAF1, which unleashes a molecular cascade that promotes expansion of breast tumor-initiating cells and cancer progression.
Two drugs slash breast cancer stem cell population
The team tested five anti-cancer drugs against a culture of breast cancer cells and in tumor samples of human breast cancer in a mouse model. Sorafenib, a RAF inhibitor also known as Nexavar, eliminated more cancer stem cells and blocked tumor formation better than the other four.
Sorafenib inhibits multiple targets, so the researchers also tested an experimental drug called AZD6244, which specifically inhibits the MEK-ERK kinase cascade launched by RAF1. They found the drug eliminates EZH2-promoted breast cancer stem cells and blocks the formation of precancerous mammospheres.
"The drugs' inhibition of the breast tumor-initiating cells reveals a previously unidentified therapeutic effect for RAF1-ERK inhibitors to prevent breast cancer progression," Hung said. AZD6244 is being tested in multiple clinical trials, he noted, and it will be interesting to see whether the cancer-stem-cell-killing ability will be induced in those trials.
Hunting down a dangerous pathway
Breast cancer stem cells can be sorted from other primary cancer cells by the presence of the surface protein CD44 and low or absent CD24 in tumor cells.
The researchers found that high expression of EZH2 in breast cancer stem cells reduced the levels of the tumor suppressor RAD1 and correlated with high-grade tumors in a sample of 168 human breast cancer tumors. It also increased the number of tumor-initiating cells in culture.
EZH2 also is heavily expressed, and RAD1 diminished, by lack of oxygen in the tumor's environment, which causes activation of the HIF1a(alpha) protein. HIF1a(alpha), the researchers found, activates the EZH2 gene by binding to the gene's promoter region.
With RAD1 unable to repair damage, amplified RAF1 triggers the MEK-ERK-ß-Catenin pathway, a well-known cancer promoting molecular pathway. The team showed EZH1 enhances this signaling pathway, which they found correlates with breast cancer progression.
In December, Hung and colleagues published a paper in Nature Cell Biology showing that the enzyme CDK1 shuts down EZH2.
Research was funded by grants from the National Cancer Institute, including those for MD Anderson's Specialized Program in Research Excellence (SPORE) for breast cancer and MD Anderson's cancer center support grant; the U.S. Department of Defense, the National Science Council of Taiwan, the Cancer Center of Excellence in Taiwan, National Breast Cancer Foundation, Inc., Kadoorie Charitable Foundation, Beast Cancer Research Foundation and the MD Anderson-China Medical University and Hospital Sister Institution Fund.
Co-authors with Hun, who also is MD Anderson vice president of basic research, are lead author Chun-Ju Chang, Ph.D., Jer-Yen Yang, Ph.D., Weiya Xia, M.D., Chun-Te Chen, Xiaoming Xie, Ph.D., Chi-Hong Chao, Ph.D., and Jung-Mao Hsu, all of MD Anderson's Department of Molecular and Cellular Oncology; Wendy Woodward, M.D., Ph.D., MD Anderson's Department of Radiation Oncology; and Gabriel Hortobagyi, M.D., of MD Anderson's Department of Breast Medical Oncology. Hsu is a student in The University of Texas Graduate School of Biomedical Sciences, a joint program of MD Anderson and The University of Texas Health Science Center at Houston (UTHealth).
He also is affiliated with the Center for Molecular Medicine and the Graduate Institute of Cancer Biology, both of the China Medical University Hospital in Taichung, Taiwan and with Asia University in Taichung.
About MD Anderson
The University of Texas MD Anderson Cancer Center in Houston ranks as one of the world's most respected centers focused on cancer patient care, research, education and prevention. MD Anderson is one of only 40 comprehensive cancer centers designated by the National Cancer Institute. For seven of the past nine years, including 2010, MD Anderson has ranked No. 1 in cancer care in "America's Best Hospitals," a survey published annually in U.S. News & World Report.
Scott Merville | EurekAlert!
A Map of the Cell’s Power Station
18.08.2017 | Albert-Ludwigs-Universität Freiburg im Breisgau
On the way to developing a new active ingredient against chronic infections
18.08.2017 | Deutsches Zentrum für Infektionsforschung
Whether you call it effervescent, fizzy, or sparkling, carbonated water is making a comeback as a beverage. Aside from quenching thirst, researchers at the University of Illinois at Urbana-Champaign have discovered a new use for these "bubbly" concoctions that will have major impact on the manufacturer of the world's thinnest, flattest, and one most useful materials -- graphene.
As graphene's popularity grows as an advanced "wonder" material, the speed and quality at which it can be manufactured will be paramount. With that in mind,...
Physicists at the University of Bonn have managed to create optical hollows and more complex patterns into which the light of a Bose-Einstein condensate flows. The creation of such highly low-loss structures for light is a prerequisite for complex light circuits, such as for quantum information processing for a new generation of computers. The researchers are now presenting their results in the journal Nature Photonics.
Light particles (photons) occur as tiny, indivisible portions. Many thousands of these light portions can be merged to form a single super-photon if they are...
For the first time, scientists have shown that circular RNA is linked to brain function. When a RNA molecule called Cdr1as was deleted from the genome of mice, the animals had problems filtering out unnecessary information – like patients suffering from neuropsychiatric disorders.
While hundreds of circular RNAs (circRNAs) are abundant in mammalian brains, one big question has remained unanswered: What are they actually good for? In the...
An experimental small satellite has successfully collected and delivered data on a key measurement for predicting changes in Earth's climate.
The Radiometer Assessment using Vertically Aligned Nanotubes (RAVAN) CubeSat was launched into low-Earth orbit on Nov. 11, 2016, in order to test new...
A study led by scientists of the Max Planck Institute for the Structure and Dynamics of Matter (MPSD) at the Center for Free-Electron Laser Science in Hamburg presents evidence of the coexistence of superconductivity and “charge-density-waves” in compounds of the poorly-studied family of bismuthates. This observation opens up new perspectives for a deeper understanding of the phenomenon of high-temperature superconductivity, a topic which is at the core of condensed matter research since more than 30 years. The paper by Nicoletti et al has been published in the PNAS.
Since the beginning of the 20th century, superconductivity had been observed in some metals at temperatures only a few degrees above the absolute zero (minus...
16.08.2017 | Event News
04.08.2017 | Event News
26.07.2017 | Event News
18.08.2017 | Life Sciences
18.08.2017 | Physics and Astronomy
18.08.2017 | Materials Sciences