Nov. 12 (Bloomberg) -- Women who don't benefit from a drug used to prevent breast cancer recurrence may have low levels of a protein linked to improved survival, U.K. researchers found.

They also found that high levels of another protein could stop the drug tamoxifen from working as it should, according to a study online today in the journal Nature. Researchers said from 25 percent to 35 percent of women with breast cancer eventually develop resistance to the medicine.

Breast cancer is the most frequently diagnosed cancer in U.S. women, excluding cancer of the skin, according to the American Cancer Society. Determining why some women develop resistance to tamoxifen and others don't may help scientists develop better treatments for the disease, the researchers said.

``For the first time, we've started to identify what the key and critical factors are that can cause drug resistance,'' said study author Jason Carroll, a researcher at Cancer Research UK Cambridge Research Institute, in a Nov. 11 conference call with reporters.

Carroll said developing tests that doctors can use on a regular basis to determine if women have low levels of the protein, called PAX2, or high levels of a competing protein, known as AIB-1, are still at least five years away.

``This is a really interesting study. It certainly helps to supplement what we already know,'' said Eric Winer, an oncologist and director of the breast oncology center at Dana-Farber Cancer Institute in Boston in a Nov. 11 telephone interview. ``It is already being looked at in the clinic as a potential strategy to overcome resistance to hormonal therapy.''

Estrogen Receptors

About two out of three breast cancers grow because they are sensitive to the hormone estrogen, according to the American Cancer Society. Tamoxifen, a generic drug, temporarily blocks estrogen receptors on breast cancer cells and stops the estrogen from binding to them. Most women receive tamoxifen for five years after they are diagnosed with breast cancer to stop the disease from returning. Over time, some women can develop resistance to the treatment, which may allow their cancer return.

Tamoxifen works by turning off a breast cancer gene, ErbB2, through the protein PAX2, the researchers said. Resistance to tamoxifen occurs when ErbB2 remains turned on because of low levels of PAX2. In women with high levels of PAX2, drug resistance can still occur if the body has higher levels of the other protein, AIB-1, they said. High levels of AIB-1 can cause PAX2 to not function properly, allowing cancer cells to divide and spread.

Learning the Mechanics

``We knew that women developed resistance to tamoxifen but previously our understanding of why this occurred could be compared with trying to fix a broken car without knowing how the engine worked,'' Carroll said in a statement issued by Cancer Research UK. ``Now we understand how all the engine parts operate and we can try to think about ways to make repairs.''

Winer said that this may be only one of the ways women become resistant to tamoxifen.

Tamoxifen is the generic name for AstraZeneca Plc's Nolvadex, no longer made in the U.S., which was developed 30 years ago. About 28,000 U.S. women receive tamoxifen as a first- line therapy, according to Cancer Research UK.

The researchers looked at 109 breast cancer tumors, all of which had been treated with tamoxifen. They found that 68 were PAX2-positive and 41 were PAX2-negative. Patients whose tumors were PAX2-positive had a ``significantly improved'' chance of survival without their cancer returning than those whose tumors were PAX2-negative.

The patients whose tumors tested PAX2-positive and also positive for AIB-1 had a worse outcome than those whose tumors were AIB-1 negative, the study found. The tumors that were PAX2- positive and AIB-1 negative had the best outcomes, they said.

Carroll said on the conference call that larger studies are needed to duplicate these findings. Once that occurs, researchers and drug companies can begin developing treatments that target these proteins, he said.

Survival rates for breast cancer have been improving for more than 20 years. More than 80 percent of women diagnosed with the cancer survive at least five years, compared with only 50 percent of women 30 years ago.

To contact the reporter on this story: Nicole Ostrow in New York at nostrow1@bloomberg.net.

Last Updated: November 12, 2008 13:00 EST