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 (ERa) bound to estrogen target genes. Under certain circumstances, as demonstrated in the case of interleukin- 1b (IL-1b) treatment, the protein Tab2 interacts with ERa/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-1b, 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 ERa, we synthesized a peptide composed of a 14-aa motif of this domain, which effectively competes with ERa/Tab2 interaction in pulldown 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.

Targeting of the adaptor protein Tab2 as a novel approach to revert tamoxifen resistance in breast cancer cells.

CUTRUPI, SANTINA;REINERI, STEFANIA;CAIZZI, LIVIA;RICCI, LAURA;FRIARD, Olivier Pierre;DE BORTOLI, Michele
2012

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 (ERa) bound to estrogen target genes. Under certain circumstances, as demonstrated in the case of interleukin- 1b (IL-1b) treatment, the protein Tab2 interacts with ERa/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-1b, 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 ERa, we synthesized a peptide composed of a 14-aa motif of this domain, which effectively competes with ERa/Tab2 interaction in pulldown 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.
31
4353
4361
http://www.nature.com/onc/index.html
Breast cancer; Tamoxifen; pharmacological resistance; cell-permeable peptide; inflammation
Cutrupi S; Reineri S; Panetto A; Grosso E; Caizzi L; Ricci L; Friard O; Agati S; Scatolini M; Chiorino G; Lykkesfeldt AE; De Bortoli M
File in questo prodotto:
File Dimensione Formato  
Cutrupi2012TargetingTAB2FreePress.pdf

accesso aperto

Tipo di file: PDF EDITORIALE
Dimensione 570.49 kB
Formato Adobe PDF
570.49 kB Adobe PDF Visualizza/Apri

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2318/127693
Citazioni
  • ???jsp.display-item.citation.pmc??? 14
  • Scopus 18
  • ???jsp.display-item.citation.isi??? 19
social impact