title: Targeting of the adaptor protein Tab2 as a novel approach to revert tamoxifen resistance in breast cancer cells.
abstract: Pharmacological resistance is a serious threat to the clinical success of hormone therapy for breast cancer. The antiproliferative response to antagonistic drugs such as tamoxifen (Tam) critically depends on the recruitment of NCoR/SMRT corepressors to estrogen receptor alpha (ERα) bound to estrogen target genes. Under certain circumstances, as demonstrated in the case of interleukin-1β (IL-1β) treatment, the protein Tab2 interacts with ERα/NCoR and causes dismissal of NCoR from these genes, leading to loss of the antiproliferative response. In Tam-resistant (TamR) ER-positive breast cancer cells, we observed that Tab2 presents a shift in mobility on sodium dodecyl sulfate--PAGE (SDS-PAGE) similar to that seen in MCF7 wt upon stimulation with IL-1β, suggesting constitutive activation. Accordingly, TamR treatment with Tab2-specific short interfering RNA, restored the antiproliferative response to Tam in these cells. As Tab2 is known to directly interact with the N-terminal domain of ERα, we synthesized a peptide composed of a 14-aa motif of this domain, which effectively competes with ERα/Tab2 interaction in pull-down and co-immunoprecipitation experiments, fused to the carrier TAT peptide to allow internalization. Treatment of TamR cells with this peptide resulted in partial recovery of the antiproliferative response to Tam, suggesting a strategy to revert pharmacological resistance in breast cancer. Silencing of Tab2 in TamR cells by siRNA caused modulation of a gene set related to the control of cell cycle and extensively connected to BRCA1 in a functional network. These genes were able to discern two groups of patients, from a published data set of Tam-treated breast cancer profiles, with significantly different disease-free survival. Altogether, our data implicate Tab2 as a mediator of resistance to endocrine therapy and as a potential new target to reverse pharmacological resistance and potentiate antiestrogen action.
authors.affiliation: Center for Molecular Systems Biology, University of Turin, Turin, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Cutrupi
authors.forename: S
authors.initials: S
authors.lastname: Reineri
authors.forename: A
authors.initials: A
authors.lastname: Panetto
authors.forename: E
authors.initials: E
authors.lastname: Grosso
authors.forename: L
authors.initials: L
authors.lastname: Caizzi
authors.forename: L
authors.initials: L
authors.lastname: Ricci
authors.forename: O
authors.initials: O
authors.lastname: Friard
authors.forename: S
authors.initials: S
authors.lastname: Agati
authors.forename: M
authors.initials: M
authors.lastname: Scatolini
authors.forename: G
authors.initials: G
authors.lastname: Chiorino
authors.forename: A E
authors.initials: AE
authors.lastname: Lykkesfeldt
authors.forename: M
authors.initials: M
authors.lastname: De Bortoli
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004965:Estrogen Antagonists / Q000627:therapeutic use*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D058990:Molecular Targeted Therapy; D034741:RNA, Small Interfering / Q000494:pharmacology; D013629:Tamoxifen / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004965:Estrogen Antagonists; D034741:RNA, Small Interfering; C410585:TAB2 protein, human; D013629:Tamoxifen