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Tamoxifen-stimulated growth of breast cancer due to p21 loss
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Tamoxifen-stimulated growth of breast cancer due to p21 loss
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Journal Article
Tamoxifen-stimulated growth of breast cancer due to p21 loss
2008
Overview
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-α, 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.
Publisher
National Academy of Sciences,National Acad Sciences
Subject
Antineoplastic Agents - pharmacology
/ Breast Neoplasms - drug therapy
/ Cyclin-Dependent Kinase Inhibitor p21 - metabolism
/ Drug Resistance, Neoplasm - genetics
/ Drugs
/ Estrogen Receptor alpha - metabolism
/ Female
/ genes
/ Humans
/ patients
/ Selective Estrogen Receptor Modulators - pharmacology
/ Studies
/ Tumors
