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Pathway links inflammation, angiogenesis and breast cancer
Date:8/13/2007

IKK 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.

For Hung, the Cell paper is part of an ongoing effort to define the cancer-inducing activity of IKK and its sibling, IKKa. He has found that the two, known to have a cancer-inducing affect working together, also have separate effects individually.

In the Cell paper, researchers show IKK does its damage working in the cytosol of the cell, the internal fluid outside of the nucleus. Together, the two kinases previously were known to free the oncoprotein nuclear factor kappa B (NF"B) from the cytosol, allowing it to move to the nucleus and activate genes that promote cancer growth.

IKKa throws switch between tumor promotion and suppression

Earlier this year in a paper published in Molecular Cell, Hung's lab established that IKKa works individually by
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Contact: Scott Merville
sdmervil@mdanderson.org
713-792-0661
University of Texas M. D. Anderson Cancer Center
Source:Eurekalert

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