Pathway Links Inflammation, Angiogenesis and Breast Cancer

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. IKKß 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 IKKß, which as a kinase works by attaching phosphate groups to other proteins.
* IKKß 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 IKKß had mean tumor volumes of 1,200 milimeters at 31 days, while those with inactive IKKß or with active IKKß and rapamycin injections to inhibit mTOR had mean volumes of less than 100 milimeters. 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 - a measure of angiogenesis.

The researchers 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 percent survival at 60 months vs. 65 percent).

Rapamycin is a powerful immune system suppressor used to protect organ transplant recipients against rejection of their new organs by suppressing mTOR. Rapamycin and similar mTOR inhibitors are in early clinical trials for a number of cancers at M. D. Anderson and elsewhere. One drug, temsirolimus, has been approved to treat renal cell carcinoma.

Hung's lab is exploring the possibility that this TNFa-driven activation of mTOR is the molecular link between obesity and heightened cancer risk. Obese mammals have high levels of TNFa secreted by their fat cells.