Because nearly three-quarters of all breast cancers are stimulated by estrogen acting at functional estrogen receptors (ER+), they are most often treated with anti-estrogen compounds that inactivate the estrogen receptor. The most common of these is the drug tamoxifen. However, only about half of ER+ breast cancers successfully respond to treatment with tamoxifen, while the other half are resistant. When tamoxifen is used in advanced disease, resistance will eventually arise in all tumors, even if they were initially sensitive. It has been reported that tamoxifen-resistant breast tumors sometimes stop growing when tamoxifen is withdrawn. Dr. Rob Michalides and colleagues from the Department of Tumor Biology at The Netherlands Cancer Institute found that activation of the enzyme protein kinase A (PKA) induced tamoxifen resistance in breast cancer cells through a unique mechanism. PKA modified the estrogen receptor in such a way that although tamoxifen could still bind, it could no longer convert the receptor to an inactive form. Instead, it acted as an estrogen receptor activator and encouraged tamoxifen-resistant cancer cell growth. Using a genetic screening technique, the researchers showed that this mechanism was also operational in patients.
The findings indicate that PKA may be a critical determinant of how ER+ breast cancers respond to tamoxifen. "This is highly relevant for breast cancer patients, since tamoxifen might induce the opposite effect when PKA is activated, stimulating ER+ tumor growth instead of inhibiting it. Such pati
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Contact: Heidi Hardman
hhardman@cell.com
617-397-2879
Cell Press
3-Jun-2004