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Low forms of cyclin E reduce breast cancer drug's effectiveness
Date:2/9/2010

l in breast cancer research.

The M. D. Anderson team 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. To test their hypothesis, the researchers exposed aromatase-overexpressing MCF-7/Ac1 breast cancer cells to the full-length form of cyclin E or to the LMW-E forms ("low forms").

"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," said Keyomarsi, the study's senior author. "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."

CDK2 Inhibitor Restores Letrozole's Growth Inhibition

After confirming that the LMW forms of cyclin E suppress the anti-proliferative 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."

The researchers also looked back at the results of another ongoing study from their group in which 128 ER+ breast cancer patients were treated with an aromatase inhibitor. "Of those, 100 expressed normal levels of wild-type cyclin E, and 28 overexpressed the low forms," Keyomarsi said. "When we looked at recurrence, three of the hundred with wild-type cyclin E had experienced a recurrence compared to four of the twenty-eight with the low forms. That in itself tells us there is a huge difference between the two groups of patients based on the pattern of expression of normal versus low forms of cyclin E."

Of the seven patients who had a recurrence, six had high levels of
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Contact: Laura Sussman
lsussman@mdanderson.org
713-745-2457
University of Texas M. D. Anderson Cancer Center
Source:Eurekalert  

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