title: Med1 plays a critical role in the development of tamoxifen resistance.
abstract: Understanding the molecular pathways that contribute to the development of tamoxifen resistance is a critical research priority as acquired tamoxifen resistance is the principal cause of poor prognosis and death of patients with originally good prognosis hormone-responsive breast tumors. In this report, we provide evidence that Med1, an important subunit of mediator coactivator complex, is spontaneously upregulated during acquired tamoxifen-resistance development potentiating agonist activities of tamoxifen. Phosphorylated Med1 and estrogen receptor (ER) are abundant in tamoxifen-resistant breast cancer cells due to persistent activation of extracellular signal-regulated kinases. Mechanistically, phosphorylated Med1 exhibits nuclear accumulation, increased interaction with ER and higher tamoxifen-induced recruitment to ER-responsive promoters, which is abrogated by inhibition of Med1 phosphorylation. Stable knockdown of Med1 in tamoxifen-resistant cells not only reverses tamoxifen resistance in vitro but also in vivo. Finally, higher expression levels of Med1 in the tumor significantly correlated with tamoxifen resistance in ER-positive breast cancer patients on adjuvant tamoxifen monotherapy. In silico analysis of breast cancer, utilizing published profiling studies showed that Med1 is overexpressed in aggressive subsets. These findings provide what we believe is the first evidence for a critical role for Med1 in tamoxifen resistance and identify this coactivator protein as an essential effector of the tamoxifen-induced breast cancer growth.
authors.affiliation: Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Johns Hopkins University School of Medicine, 1650 Orleans Street, CRB 1, Room 145, Baltimore, MD 21231, USA.
authors.forename: Arumugam
authors.initials: A
authors.lastname: Nagalingam
authors.forename: Mourad
authors.initials: M
authors.lastname: Tighiouart
authors.forename: Lisa
authors.initials: L
authors.lastname: Ryden
authors.forename: Leena
authors.initials: L
authors.lastname: Joseph
authors.forename: Goran
authors.initials: G
authors.lastname: Landberg
authors.forename: Neeraj K
authors.initials: NK
authors.lastname: Saxena
authors.forename: Dipali
authors.initials: D
authors.lastname: Sharma
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D015153:Blotting, Western; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D056913:Mediator Complex Subunit 1 / Q000378:metabolism / Q000502:physiology*; D008856:Microscopy, Fluorescence; D010766:Phosphorylation; D011960:Receptors, Estrogen / Q000502:physiology; D013629:Tamoxifen / Q000494:pharmacology*
chemical_list: D018931:Antineoplastic Agents, Hormonal; C538855:MED1 protein, human; D056913:Mediator Complex Subunit 1; D011960:Receptors, Estrogen; D013629:Tamoxifen; D048049:Extracellular Signal-Regulated MAP Kinases