(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
