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Feb 18, 2013

How Aggressive Breast Tumors and Mitochondrial Mutations Are Linked

  • A new weapon in the battle against breast cancer may be on its way. Researchers from the Scripps Research Institute (TSRI) have identified a mechanism through which mitochondria control tumor aggressiveness. The team says they've developed a treatment that inhibits cancer progression and can prolong life when tested in mice.

    The TSRI laboratory of associate professor Brunhilde H. Felding, Ph.D., studies cancer, especially the mechanisms that control metastasis. Past research suggested that mutations affecting mitochondria, which are key to energy production in cells, strongly influence whether a tumor becomes aggressive, but the mechanism was not clear.

    "We decided to investigate a specific protein complex, called mitochondrial complex I, that critically determines the energy output of cellular respiration," said the study's first author, Antonio F. Santidrian, Ph.D., a research associate in Dr. Felding's laboratory. To do this, the group partnered with Akemi and Takao Yagi at TSRI, who specialize in complex I research. Using reagents from the Yagi group, the Felding team discovered that the balance of key metabolic cofactors processed by complex I—specifically, nicotinamide adenine dinucleotide (NAD+) and NADH, the form it takes after accepting a key electron in the energy production cycle—was disturbed in aggressive breast cancer cells.

    To find out if the balance of NAD+ and NADH was critical for tumor cell behavior, the team inserted a yeast gene into cancer cells that caused a shift toward more NAD+. This shift caused the tumor cells to become less aggressive. To confirm and extend the initial findings, the team altered genes tied to NAD+ production. The resulting shift again showed that higher NADH levels meant more aggressive tumors, while increased NAD+ had the opposite effect.

    The team then sought out a way to enhance the critical NAD+ level therapeutically by exploring what would happen if mice with breast cancer (of the transgenic MMTV-PyMT model) were fed water spiked with nicotinamide, a precursor for NAD+ production. The scientists found that enhancing the NAD+/NADH balance through the nicotinamide treatment inhibited metastasis, and the mice lived longer.

    "In animal models at various stages, we see that we can actually prevent progression of the disease," said Dr. Felding.

    Now the group is working toward human trials to learn whether nicotinamide or other NAD+ precursors will have similar results in humans. Since NAD+ precursors are already used for other purposes, such as controlling cholesterol levels, the team hopes that achieving approval for human clinical trials will be simpler than is normally the case.

    "It is not a totally new treatment that would need to be tested for toxicity and side effects like a new drug," said Dr. Felding. "And we already know the precursors can be easily ingested."

    The team says that such a treatment, should it prove to be as effective in humans as it is in mice, could benefit people at risk of developing aggressive breast cancer, offer complimentary treatment to chemo and radiation therapy to avoid disease recurrence, and maybe even provide a preventive treatment for women with a family history of breast cancer.

    The team describes its results in an article published online ahead of print by the Journal of Clinical Investigation titled "Mitochondrial Complex I activity and NAD+/NADH balance regulate breast cancer progression".


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