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Pathway links inflammation, angiogenesis and breast cancer

HOUSTON - A well-known inflammatory protein spawns an enzyme that inactivates two tumor-suppressing genes, ultimately triggering production of new blood vessels to nourish breast cancer cells, researchers at The University of Texas M. D. Anderson Cancer Center report in the August edition of the journal Cell.

"This is a completely new pathway for inflammation-induced cancer and may provide new targets for clinical intervention," senior author Mien-Chie Hung, Ph.D., professor and chair of M. D. Anderson's Department of Molecular and Cellular Oncology says of the chain of events described in the journal.

Inflammation is linked to breast cancer, liver cancer and cancers of the gastrointestinal tract. The research team set out to discover whether angiogenesis - the creation of new blood vessels - plays a role in cancer formation related to the inflammatory protein Tumor Necrosis Factor alpha (TNFa).

"What we found is a previously unrecognized role for IKKbeta, a protein kinase activated by TNFa," Hung says. IKK inactivates a cancer-suppressing protein complex, which frees a cancer-inducing pathway to generate new blood vessels to supply tumors.

The chain of events, painstakingly worked out by Hung, first author and doctoral student Dung-Fang Lee, and colleagues works like this:

  • TNFa activates IKK, which as a kinase works by attaching phosphate groups to other proteins.

  • IKK phosphorylates tuberous sclerosis 1 (TSC1) blocking it from working with its ally, tuberous sclerosis 2, to repress the mammalian target of rapamycin (mTOR) pathway.

  • With the tumor suppressors inactivated, mTOR is freed to produce vascular endothelial growth factor (VEGF), which creates new blood vessels to feed breast cancer.

The team confirmed the lab findings in mice. Mice with active IKK had mean tumor volumes of 1,200 milimeters at 31 days, while those with inactive IKK or with ac
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Contact: Scott Merville
sdmervil@mdanderson.org
713-792-0661
University of Texas M. D. Anderson Cancer Center
9-Aug-2007


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