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Protein related to aging holds breast cancer clues
Date:1/27/2011

ER/PR positive breast tumors, the most common type of breast cancer in postmenopausal women.

These tumors also exhibited increased levels of damaging free radicals and "reactive oxygen species" (ROS) including superoxide, the primary metabolite of oxygen in the mitochondria which provided an important clue as to how Sirt3 deficiency might permit these tumors to develop.

"The mechanism, at least in part, for why these mice develop receptor positive breast cancer is altered mitochondrial ROS, including superoxide," Gius said.

But how deficiency in a longevity gene led to increased ROS was not clear.

Since superoxide is generally removed from the cell with the help of a detoxifying enzyme called manganese superoxide dismutase (MnSOD), Gius hypothesized that the Sirt3 deficiency may abnormally regulate MnSOD.

In the current study, the researchers show that Sirt3 knockout mice have decreased MnSOD activity despite having normal levels of the protein.

Gius and colleagues determined that the MnSOD in Sirt3 knockout mice was abnormally modified (with a chemical "acetyl" group) at a specific amino acid (lysine 122).

This aberrant modification of MnSOD reduced the enzyme's ability to detoxify superoxide and appeared to explain the increase in ROS in Sirt3 knockout mouse tumors.

"These results suggest that aberrant regulation of MnSOD plays a role in receptor positive breast cancer," said Gius.

Gius and colleagues also developed an antibody that can assess the acetylation status of MnSOD, which he says can potentially be used "to screen breast tissue samples to determine what women are at risk for (receptor positive) cancer or for recurrence because of this dysregulation of MnSOD."

Additionally, agents that target the acetylation of this amino acid on MnSOD may be useful as chemopreventive therapies in women at risk of these cancers and of recurrence, he noted.


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Contact: Melissa Marino
melissa.marino@vanderbilt.edu
615-322-4747
Vanderbilt University Medical Center
Source:Eurekalert

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