| Literature DB >> 18162533 |
Abde M Abukhdeir1, Michele I Vitolo, Pedram Argani, Angelo M De Marzo, Bedri Karakas, Hiroyuki Konishi, John P Gustin, Josh Lauring, Joseph P Garay, Courtney Pendleton, Yuko Konishi, Brian G Blair, Keith Brenner, Elizabeth Garrett-Mayer, Hetty Carraway, Kurtis E Bachman, Ben Ho Park.
Abstract
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-alpha, 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.Entities:
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Year: 2007 PMID： 18162533 PMCID： PMC2224203 DOI： 10.1073/pnas.0710887105
Source DB: PubMed Journal: Proc Natl Acad Sci U S A ISSN： 0027-8424 Impact factor: 11.205