Lani
02-17-2011, 12:47 PM
Overabundance of Protein Expands Breast Cancer Stem Cells; Two Drugs Block Cancer-Promoting Chain of Events
[ScienceDaily]
ScienceDaily (Feb. 16, 2011) — 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.
ABSTRACT: EZH2 Promotes Expansion of Breast Tumor Initiating Cells through Activation of RAF1-á-Catenin Signaling
[Cancer Cell]
It has been proposed that an aggressive secondary cancer stem cell population arises from a primary cancer stem cell population through acquisition of additional genetic mutations and drives cancer progression. Overexpression of Polycomb protein EZH2, essential in stem cell self-renewal, has been linked to breast cancer progression. However, critical mechanism linking increased EZH2 expression to BTIC (breast tumor initiating cell) regulation and cancer progression remains unclear. Here, we identify a mechanism in which EZH2 expression-mediated downregulation of DNA damage repair leads to accumulation of recurrent RAF1 gene amplification in BTICs, which activates p-ERK-β-catenin signaling to promote BTIC expansion. We further reveal that AZD6244, a clinical trial drug that inhibits RAF1-ERK signaling, could prevent breast cancer progression by eliminating BTICs.
[ScienceDaily]
ScienceDaily (Feb. 16, 2011) — 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.
ABSTRACT: EZH2 Promotes Expansion of Breast Tumor Initiating Cells through Activation of RAF1-á-Catenin Signaling
[Cancer Cell]
It has been proposed that an aggressive secondary cancer stem cell population arises from a primary cancer stem cell population through acquisition of additional genetic mutations and drives cancer progression. Overexpression of Polycomb protein EZH2, essential in stem cell self-renewal, has been linked to breast cancer progression. However, critical mechanism linking increased EZH2 expression to BTIC (breast tumor initiating cell) regulation and cancer progression remains unclear. Here, we identify a mechanism in which EZH2 expression-mediated downregulation of DNA damage repair leads to accumulation of recurrent RAF1 gene amplification in BTICs, which activates p-ERK-β-catenin signaling to promote BTIC expansion. We further reveal that AZD6244, a clinical trial drug that inhibits RAF1-ERK signaling, could prevent breast cancer progression by eliminating BTICs.