Scientists at the University of California, San Francisco (UCSF) have discovered the molecular basis for tamoxifen resistance to breast cancer and found a potential way to defeat it.
In the last three decades, thousands of women with breast cancer have taken the drug tamoxifen, only to discover that the therapy doesn’t work, either because their tumours do not respond to the treatment at all, or because they develop resistance to it over time.
“Understanding the mechanism of tamoxifen resistance and how to defeat it may help a large number of women with hormone-resistant breast cancer,” said UCSF oncologist Pamela Munster, MD, Munster.
“It may lead quickly to new, more effective treatment strategies and may help to identify biomarkers to help to gauge whether or not someone will respond to treatment in the first place,” she stated.
While doctors have documented cases of tamoxifen resistance in the clinic for decades, nobody knew exactly how the cells were able to acquire resistance.
Many scientists thought that genetics were to blame – certain variations in one’s DNA that would pass from parents to children and make one more likely to develop a tamoxifen-resistant form of breast cancer. According to Munster, that is not the case.
“We always thought that resistance was genetic. But now we have discovered that cells have a way of developing resistance by means of epigenetic modification,” said Munster.
Epigenetics is a general phenomenon in biology that explains how some cells, tissues, and whole organisms can acquire traits that go beyond mere genetic differences.
Rather than genes being mutated or changed and then passed on to offspring, which is the domain of genetics, epigenetic changes are not in the genes themselves but in their levels of expression and activity.
Munster and her colleagues discovered that when cancer cells are fed tamoxifen, they sometimes respond by elevating expression of a gene known as AKT.
AKT is a “survival” gene that in normal situations helps to stimulate growth and proliferation of cells and prevent cells from dying.
In breast cancer, however, it can become overactive and confer resistance by allowing the cancer cells to continue to use the estrogen receptor even in the presence of tamoxifen.
The good news clinically, said Munster, is that several existing compounds known as histone deacetylase inhibitors directly target AKT.
She and her colleagues showed that when cells in the laboratory are fed these histone deacytalase inhibitors, their levels of AKT are knocked back. Giving the same cells tamoxifen at the same time dramatically curtails the ability of the cells to proliferate.
In clinical studies published earlier this year, Munster and her colleagues also showed that taking both drugs together can reverse tamoxifen resistance.
This approach will have to prove safe and effective in additional, large-scale clinical trials before it becomes generally available.
The results were presented at the AACR-NCI-EORTC International Conference in San Francisco.