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Aug 9, 2007

Mechanism for Inactivation of Tumor-Suppressing Genes by TNFa Discovered

  • University of Texas M. D. Anderson Cancer Center researchers discovered that a well-known inflammatory protein, tumor necrosis factor alpha (TNFa), spawns an enzyme that inactivates two tumor-suppressing genes in mice, ultimately triggering production of new blood vessels to nourish breast cancer cells.

    “What we found is a previously unrecognized role for IKKß, a protein kinase activated by TNFa,” says senior author Mien-Chie Hung, Ph.D., professor and chair of M. D. Anderson’s department of molecular and cellular oncology.

    The scientists observed that TNFa activates IKKß, which as a kinase, works by attaching phosphate groups to other proteins. IKKß then phosphorylates tuberous sclerosis 1 (TSC1) blocking it from working with 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.

    In the study, mice with active IKKß had mean tumor volumes of 1,200 mm at 31 days, while those with inactive IKKß or with active IKKß and injections of rapamycin, an immune system suppressor made by Wyeth used to protect organ transplant recipients to inhibit mTOR,  had mean volumes of less than 100 mm.

    Similar disparate tumor sizes were found when the tumor-suppressing TSC1 was inactivated. Tumors with TSC1 inactivated also were found to have greater blood vessel density.

    The researchers further tested the theory by analyzing breast cancer tumors from 116 patients. They found breast cancer patients whose tumors had the TSC1/TSC2 tumor suppressor complex blocked by phosphorylation did not survive as long as those with an active TSC1/TSC2 (46% survival at 60 months versus 65%).

    The study will be published in the August 10 edition of Cell.



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