title: Tamoxifen-stimulated growth of breast cancer due to p21 loss.
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.
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
authors.forename: Abde M
authors.initials: AM
authors.lastname: Abukhdeir
authors.forename: Michele I
authors.initials: MI
authors.lastname: Vitolo
authors.forename: Pedram
authors.initials: P
authors.lastname: Argani
authors.forename: Angelo M
authors.initials: AM
authors.lastname: De Marzo
authors.forename: Bedri
authors.initials: B
authors.lastname: Karakas
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Konishi
authors.forename: John P
authors.initials: JP
authors.lastname: Gustin
authors.forename: Josh
authors.initials: J
authors.lastname: Lauring
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Garay
authors.forename: Courtney
authors.initials: C
authors.lastname: Pendleton
authors.forename: Yuko
authors.initials: Y
authors.lastname: Konishi
authors.forename: Brian G
authors.initials: BG
authors.lastname: Blair
authors.forename: Keith
authors.initials: K
authors.lastname: Brenner
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Garrett-Mayer
authors.forename: Hetty
authors.initials: H
authors.lastname: Carraway
authors.forename: Kurtis E
authors.initials: KE
authors.lastname: Bachman
authors.forename: Ben Ho
authors.initials: BH
authors.lastname: Park
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism*; D019175:DNA Methylation; D004252:DNA Mutational Analysis; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005260:Female; D006801:Humans; D008875:Middle Aged; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology; D013629:Tamoxifen / Q000494:pharmacology*; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D047628:Estrogen Receptor alpha; D020845:Selective Estrogen Receptor Modulators; D013629:Tamoxifen