Vitamin A May Lead to Drug for Triple Negative

Retinoic acid, a component of Vitamin A, has the potential to treat breast cancer, including triple negative, according to research in the June 24, 2009 issue of the journal Cell.

The main story being reported is on retinoic acid’s influence on hormone-positive breast cancer, helping the body balance the effect of hormones.  Here’s how it goes: estrogen makes cells grow rapidly; retinoic acid slows that process down.  And that's an important story.

But researchers say retinoic acid can even help cancers that are not fueled by estrogen—that is, hormone-negative cancers such as triple negative.  And that's a bigger story, because at this point triple negative breast cancer has no drug therapy, as the primary breast cancer drugs, tamoxifen and Arimidex, are designed to combat estrogen, which is not a factor in estrogen-negative cancer.

From a news release from the University of Chicago, whose scientists conducted the research: 

"Understanding all the components of this process could be used against breast cancer care in three ways," said study leader, Kevin White, PhD, professor of human genetics and director of the Institute for Genomics and System Biology at the University of Chicago. "It suggests new ways to think about preventing the disease in those at high risk. It offers molecular tools that could provide a more precise diagnosis and predict outcomes. It could also be used to enhance current therapies, making existing drugs, such as tamoxifen, that selectively block estrogen's effects even more powerful, or even to develop new anti-cancer drugs."

White's team studies the effects of nuclear receptors, a class of proteins found within cells that control the response to various hormones. When a hormone enters a cell and connects with its receptor, that receptor alters the pattern of expression of specific genes--often hundreds or more.

But, they note, cancers that do not respond to hormones can also be affected.

This competition between the two signals also provides a new tool to predict outcomes. The researchers compared the effects of retinoic acid on tissues from 295 breast cancer patients against the results from their initial study using a typical breast cancer cell line. They found that the more responsive a tumor was to retinoic acid, the better the odds of long-term relapse-free survival.

Some of the genes that respond to retinoic acid were expressed even in difficult-to-treat tumors, such as those that do not have estrogen receptors or the molecule targeted by the drug Herceptin, the so-called double- or triple-negative breast cancers. "Some of these genes may provide new drug targets," White said.

Although retinoic acid is approved for treatment of leukemia, it can be quite toxic and patients can develop resistance to the drug. This study suggests a long series of downstream targets that are activated by the RA receptor.

"The goal would be to develop drugs that could activate these cancer-inhibiting targets," said White. “Retinoic acid itself is probably not the solution because of its side effects and metabolic byproducts," He cautioned, "but our results provide a molecular justification for finding ways to overcome its limitations in the clinic.”