| Autor: |
Abukhdeir, Abde M., Vitolo, Michele I., Argani, Pedram, De Marzo, Angelo M., Karakas, Bedri, Hiroyuki Konishi, Gustin, John P., Lauring, Josh, Garay, Joseph P., Pendleton, Courtney, Yuko Konishi, Blair, Brian G., Brenner, Keith, Garrett-Mayer, Elizabeth, Carraway, Hetty, Bachman, Kurtis E., Ben Ho Park |
| Předmět: |
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| Zdroj: |
Proceedings of the National Academy of Sciences of the United States of America; 1/8/2008, Vol. 105 Issue 1, p288-293, 6p, 4 Diagrams |
| Abstrakt: |
Tamoxifen is widely used for the treatment of hormonally responsive breast cancers. However, some resistant breast cancers develop a growth proliferative response to this drug, as evidenced by tumor regression upon its withdrawal. To elucidate the molecular mediators of this paradox, tissue samples from a patient with tamoxifen-stimulated breast cancer were analyzed. These studies revealed that loss of the cyclin-dependent kinase inhibitor p21 was associated with a tamoxifen growth-inducing phenotype. Immortalized human breast epithelial cells with somatic deletion of the p21 gene were then generated and displayed a growth proliferative response to tamoxifen, whereas p21 wild-type cells demonstrated growth inhibition upon tamoxifen exposure. Mutational and biochemical analyses revealed that loss of p21's cyclin-dependent kinase inhibitory property results in hyperphosphorylation of estrogen receptor-u, with subsequent increased gene expression of estrogen receptor-regulated genes. These data reveal a previously uncharacterized molecular mechanism of tamoxifen resistance and have potential clinical implications for the management of tamoxifen-resistant breast cancers. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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