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DURHAM, N.C. – Scientists at the Duke Comprehensive Cancer Center have discovered a faster and more direct way in which the drug tamoxifen signals damaged breast cells to die. They are manipulating this pathway with newer and safer drugs designed to prevent breast cancer without triggering the hot flashes and other side effects of tamoxifen.

Tamoxifen is currently the front-line drug to prevent breast cancer, but millions of women do not take it because of its potential to cause hot flashes, mood swings, sleep changes, blood clots and stroke, said Victoria Seewaldt, M.D., lead author of a tamoxifen study published in the November 18, 2004, issue of the journal Oncogene.
Seewaldt's research team set out to understand how tamoxifen kills damaged breast cells before they have the chance to become cancerous. They found that tamoxifen acts through a second, fast-acting pathway inside breast cells that is far more direct than the already known slow-acting pathway which activates genes inside the nucleus.

Tamoxifen's side effects are thought to be caused when genes in the nucleus are activated, so using drugs that target only the fast-acting pathway could eliminate unwanted side effects, she said.

"Our ability to prevent breast cancer is highly dependent upon developing ways to kill damaged cells before they have a chance to become cancerous. But at the same time, we need to find drugs that have acceptable side effects." said Seewaldt, director of the Breast Cancer Prevention Program at Duke. "The discovery of this new pathway enhances our ability to find better drugs that utilize this fast-acting pathway and thus avoid triggering the lengthy and complex cellular pathways that trigger side effects."

Toward that end, Seewaldt and her cancer prevention research team led by Eric Dietze, Ph.D, Michelle Bowie and Victoria Scott are testing several potential drugs in the laboratory for their ability to kill damaged breast cells using the newly discovered rapid pathway.

In addition, Seewaldt's new breast chemoprevention clinic uses a novel technique to identify abnormal breast cells and track whether prevention agents – such as tamoxifen or aromatase inhibitors --are eradicating damaged cells in an individual woman's breasts. The new technique enables Seewaldt and her team to rapidly develop and test new prevention agents that are identified in their laboratory.

"As scientists, we don't really understand how the various agents we give to patients actually repair what is malfunctioning inside breast cells," said Seewaldt. "Now, we've shown a novel way in which tamoxifen works inside breast cells, and we can use this knowledge to manipulate breast cells with newer drugs. It could potentially change the way we approach breast cancer prevention for millions of women."

Until now, scientists have believed that tamoxifen entered cells only in one way: by slowly leaking through a breast cell's outer membrane, idling in the cell until tamoxifen encounters an estrogen receptor in the nucleus, binding to it, and activating genes to cause cell-suicide. This process occurs only in breast cancer cells with high levels of estrogen (called "estrogen receptor-positive breast cancer).

But little was know about how tamoxifen acts to prevent breast cancer in normal breast cells at risk for becoming cancerous. Paradoxically, normal breast cells do not have high levels of estrogen receptor, said Seewaldt.

In studying how tamoxifen works inside these cells, Seewaldt and her colleagues found that it kills damaged normal breast cells through this newly discovered fast-acting pathway that avoids the nuclear estrogen receptor altogether.

In its fast-acting mechanism, tamoxifen binds to the surface of damaged normal breast cells and rapidly sends signals to a protein inside the cell called AKT. This protein is critical in regulating cellular thermostats – known as mitochondria – that decide how and when a damaged cell dies. Results of this study, led by Eric Dietze, Ph.D., were published in the May 6, 2004, issue of the journal Oncogene.

In the most recently published Oncogene study, Seewaldt's team investigated how a protein that is downstream from AKT, called CBP, triggers a second protein called IRF-1 to ultimately cause damaged cells to voluntarily commit suicide – a process called apoptosis.

This rapid response pathway that activates CBP and IRF-1 has never been shown before, said Seewaldt. The pathway is particularly interestingly because IRF-1 is one of the genes that is also known to be important for halting the production of breast milk when a women stops breast feeding, she said. Pregnancy before the age of 30 and breast feeding are both known to be protective against breast cancer, said Seewaldt, and there appears to be a connection between the genes activated by tamoxifen, breast feeding and pregnancy.

The research was funded by the National Cancer Institute, the National Institutes of Health, the Susan G. Komen Foundation, the Department of Defense Breast Cancer Program, and the Jimmy V-Foundation.