In the December 15, 2010, issue of the journal Cancer Research, the scientists, from at Kimmel Cancer Center at Jefferson University (Philadelphia, PA, USA), reported they can now conclusively demonstrate that an inflammatory process within the breast itself promotes growth of breast cancer stem cells responsible for tumor development. They also show that inactivating this inflammation selectively within the breast reduced activity of these stem cells, and blocked breast cancer from forming.
"These studies show for the first time that inactivating the NFKB inflammatory pathway in the breast epithelium blocks the onset and progression of breast cancer in living animals," said Richard G. Pestell, MD, PhD, director, Kimmel Cancer Center, and chairman of cancer biology.
"This finding has clinical implications," remarked coauthor Michael Lisanti, leader of the Program in Molecular Biology and Genetics of Cancer at Jefferson. "Suppressing the whole body's inflammatory process has side effects. These studies provide the rationale for more selective anti-inflammatory therapy directed just to the breast."
Dr. Pestell and his colleagues showed the "canonical" NFKB pathway promotes breast cancer development: the first "insult" is provided by the HER2 oncogene, which then activates NFKB (nuclear factor kappa-light-chain-enhancer of activated B cells). NFKB triggers inflammation via tumor-associated macrophages (TAM), which produce tumor growth-promoting factors.
Although inflammation, mediated by NFKB, has long been thought to be important in breast cancer development, the hypothesis had been untestable because NF-κB is vital to embryonic development, according to Dr. Pestell. "When you try to knock out NFKB genes in mice, they die." He addressed this problem by creating a mouse in which the inflammatory system within the adult animal's normal breast could be regulated. This allows selective inactivation of NFKB in different cell types, and took 12 years to accomplish, Dr. Pestell reported. "These mice have five cointegrated transgenes."
The mice are programmed to develop breast cancer; however, the researchers discovered that if they selectively blocked inflammation just in the breast, tumors would not develop. "This is a very novel finding," Dr. Pestell stated.
The investigators then demonstrated that this inactivation also reduced the number of cancer stem cells in the breast. "That told us that inflammation, through the action of NF-κB, is important to the growth and activity of cancer stem cells," Dr. Pestell said. "The transgenic mice are a new technology that can be used by the scientists and the pharmaceutical industry to understand the role of NFKB in different diseases including heart disease, neurodegeneration, and other cancers."
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Kimmel Cancer Center at Jefferson University
