Breast Cancer Drug Thwarted by Protein
Reported February 11, 2010
(Ivanhoe Newswire) — Overexpression of certain forms of the protein cyclin E renders the drug letrozole ineffective among women with estrogen-receptor-positive (ER+) breast cancers.
Cyclin E is one of the proteins that regulates the cell cycle, influencing how rapidly a cell divides. In cancer cells, cyclin E is converted to low-molecular weight forms, something that does not happen in normal cells. Elevated levels of LMW-E have been linked to uncontrolled cell proliferation and a poor outcome in breast cancer patients.
The M. D. Anderson research, led by Khandan Keyomarsi, Ph.D., professor of Experimental Radiation Oncology, found evidence that women whose cancers express the LMW-E are more likely to develop resistance to letrozole. However, their research also showed that treating breast cancer cells with a cyclin-dependent kinase 2 (CDK2) inhibitor can reverse letrozole resistance.
The researchers estimated that approximately 70 percent of all breast cancer patients are estrogen receptor positive. Of these, many are post-menopausal and would therefore be candidates to receive an aromatase inhibitor as maintenance therapy. Aromatase inhibitors can reduce the risk of early metastasis among postmenopausal women with ER+ breast cancer. However, not every patient responds to aromatase inhibitors, and those who do will develop resistance to the drugs over time.
They hypothesized that ER+ breast cancer patients whose tumors express the LMW forms of cyclin E would be less responsive to treatment with an aromatase inhibitor.
“We found that we could negate the growth inhibitory effects of letrozole with the low forms of cyclin E but not with the wild-type cyclin E,” Dr. Keyomarsi was quoted as saying. “The mechanism behind this is that the low forms of cyclin E increase the activity of the cyclin E complex, and this complex is what mediates the negative effects.”
After confirming that the LMW forms of cyclin E suppress the effects of letrozole, the researchers examined whether a CDK2 inhibitor could reverse the drug resistance in the unresponsive breast cancer cells.
“We challenged the aromatase-overexpressing cells with either the wild-type or the low forms of cyclin E and then treated them with the CDK2 inhibitor roscovitine,” Keyomarsi said. “When we did that, we could kill all the cells.”
“I believe that in the very near future we will be able to take advantage of the knowledge we now have about the low forms of cyclin E and identify the patients who have these forms and devise a personalized treatment,” Dr. Keyomarsi said.
SOURCE: Clinical Cancer Research, February 9, 2010