WEDNESDAY, Nov. 12, 2008 (HealthDay News) -- As many as 35 percent of women who take tamoxifen to prevent the return of breast cancer do not respond to the drug -- and now scientists think they know why.
A battle between proteins to turn a breast cancer gene off or on determines if tamoxifen works or not, the scientists report. The finding could be used to spot those women who won't respond to the drug, and it may even lead to new therapies.
"Given the fact that tamoxifen is such a commonly prescribed drug for the treatment of breast cancer, understanding how it works and what happens when it fails is critical to making better drugs," Jason Carroll, from the Cancer Research UK Cambridge Research Institute, said during a Tuesday teleconference on the research.
His team published its report in the Nov. 12 online edition of Nature.
Tamoxifen resistance is a significant problem, affecting 25 percent to 35 percent of breast cancer patients, the authors said.
Now, the puzzle of resistance to the drug may be solved.
"For tamoxifen to work, it has to be able to switch off a very powerful cancer gene," Carroll said. Tamoxifen stops tumor growth by binding to the estrogen receptor and blocking the HER-2 gene, which otherwise causes cancer cells to divide. "If this switch fails, cancer cells become tamoxifen-resistant and tamoxifen is no longer effective," Carroll explained.
In the study, Carroll's team found how this gene can be switched on and off.
The switch for the HER2 gene is hidden within the gene, Carroll said. That switch is a signaling molecule called PAX2. "PAX2 is the handle that keeps HER2 switched off," he said.
If PAX2 isn't there -- or is forced out by another protein called AIB-1 -- the switch fails, Carroll said. "It's a tug of war," he said. "It's a competition between PAX2 and AIB-1. The balance between PAX2 and AIB-1 determines whether HER2 is switched on or switched off, and this directly dictates whether tamoxifen works or not."
The researchers found that high levels of PAX 2 were linked to longer survival for women taking tamoxifen, while tougher, tamoxifen-resistant tumors had high levels of AIB1.
This information could be used to predict which patients are likely to respond to tamoxifen, and which patients are not likely to respond to the drug, Carroll said.
"If we can identify the women who are not going to respond to tamoxifen we can think about alternative therapies, which are probably going to be more effective for these women," Carroll said.
Dr. Len Lichtenfeld, deputy chief medical officer of the American Cancer Society, believes the finding will not have an immediate effect on treatment, but might help direct therapy in the future.
"We have learned a lot about makes a cancer cell a cancer cell, and how it works," Lichtenfeld said. "And we have also learned how to better treat breast cancer."
"Understanding these mechanisms will inevitably open up new treatment opportunities," Lichtenfeld said.
More information
For more information on breast cancer, visit the American Cancer Society.
