How Breast Cancer Cells Resist Tamoxifen
The drug tamoxifen is widely used to treat breast cancer patients, but 30 percent of people do not respond or become resistant to it.
A study by researchers at The Ohio State University Comprehensive Cancer Center explains why this happens, and it may lead to a test that identifies resistant patients.
The study found that abnormally high levels of two small molecules, called microRNA-221 (miR-221) and microRNA-222 (miR-222), contribute significantly to this problem. MicroRNAs are a family of small molecules that control the number and type of proteins that cells make.
The researchers note that these two particular microRNAs may be potential markers of tamoxifen-resistant tumors.
"If a marker of this kind were available, physicians could identify patients with tamoxifen-resistant tumors and treat them from the beginning with a more effective drug," says co-author Samson T. Jacob, professor of molecular and cellular biochemistry and of hematogy-oncology at Ohio State and co-leader of the cancer center's Experimental Therapeutics Program.
The research was reported in a recent issue of the Journal of Biological Chemistry. It was also selected as the journal's paper of the week.
"Further study of these deregulated microRNAs could also broaden our understanding of tamoxifen resistance and aid in the design of new therapeutic agents for these patients," says principal investigator Sarmila Majumder, research assistant professor of molecular and cellular biochemistry.
To begin this study, Majumder, Jacob and colleagues Kalpana Ghoshal, research assistant professor of molecular and cellular biochemistry, and Tyler Miller, a biomedical science undergraduate student, compared microRNA levels in tamoxifen resistant and tamoxifen sensitive breast cancer cells. The cancer cells represented estrogen-receptor positive, post-menopausal breast cancer, the most common form of the disease.
Eight different microRNAs showed unusually high levels in the resistant cells, with miR-221 and miR-222 increased by 13 times compared with drug-sensitive cells, the highest of all.
To learn whether these microRNAs are also elevated in humans, the researchers analyzed breast tumors from patients, choosing only those having high levels of the protein HER2. Such tumors are generally tamoxifen resistant, Jacob says. They, too, showed similarly high levels of the two microRNAs, providing more evidence that the two molecules play a role in tamoxifen resistance.
Turning again to the cell lines, the researchers boosted the level of the two molecules in tamoxifen-susceptible cells. This enabled the cells to grow in the drug's presence, a hallmark of resistance.
Last, they showed how the molecules make breast-cancer cells resistant.
It was already known that the two microRNAs regulate the amount of a protein called Kip1 in the cell. And, as the researchers expected, the tamoxifen-resistant cells had high levels of the two molecules and low levels of this protein.
In this case, the researchers boosted the amount of the protein in the drug-resistant cells. Many of the cells then died when exposed to tamoxifen, indicating an increase in drug sensitivity and providing strong evidence that high levels of the two molecules contribute to tamoxifen resistance.
"All our lines of evidence linked nicely together, it all makes sense," Jacob says. "Our findings clearly show that these two microRNAs are involved in tamoxifen resistance and warrant further study as potential markers for determining therapy," Majumder says.