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

Oncogene volume 31, pages 4353–4361 (2012)Cite this article

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A Corrigendum to this article was published on 04 October 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 (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.

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Abbreviations

4OHT:

4-OH-tamoxifen

AI:

aromatase inhibitors

AR:

androgen receptor

E2:

17β-estradiol

ERα:

estrogen receptor α

IL-1β:

inteleukin-1β

PgR:

progesterone receptor

SERMs:

selective estrogen receptor modulators

Tam:

tamoxifen

TamR:

tamoxifen-resistant cells

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Acknowledgements

This work was supported by grants from PRIN (2008PC9CFW_002) and from the Associazione Italiana per la Ricerca sul Cancro (Grant number IG9397), and in part by the public grant ‘ERSF -DOCUP 2000-2006 (Misura 3.4)’ - hitechplat project. LR is a CRT Fondazione Lagrange (Turin) fellow. AP was supported in part by the Associazione Sviluppo Piemonte (Turin). EG was a CRT Fondazione Lagrange (Turin) fellow and was supported in part by a Compagnia di San Paolo (Turin) grant and by a UICC travel fellowship.

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  1. S Cutrupi and S Reineri: These authors contributed equally to this work.

Authors and Affiliations

  1. Center for Molecular Systems Biology, University of Turin, Turin, Italy

    S Cutrupi, S Reineri, A Panetto, E Grosso, L Caizzi, L Ricci, O Friard & M De Bortoli

  2. Department of Human and Animal Biology, University of Turin, Turin, Italy

    S Cutrupi

  3. Department of Oncological Sciences, University of Turin, Turin, Italy

    S Reineri, L Caizzi, S Agati & M De Bortoli

  4. Bioindustry Park Silvano Fumero, Colleretto Giacosa, Turin, Italy

    A Panetto & L Ricci

  5. Laboratory of Cancer Genomics, Fondazione Edo ed Elvo Tempia Valenta, Biella, Italy

    E Grosso, M Scatolini & G Chiorino

  6. Department of Breast Cancer Research, Institute of Cancer Biology, Danish Cancer Society, Copenhagen, Denmark

    A E Lykkesfeldt

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Correspondence to M De Bortoli.

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Competing interests

Drs Caizzi, Agati and Ricci received compensation for this work by the Bioindustry Park Silvano Fumero S.p.A, owner of the Patent IT TO20080989. Drs Cutrupi, Reineri, Panetto and De Bortoli are inventors of the Patent IT TO20080989. Drs Grosso, Friard, Scatolini, Chiorino and Lykkesfeldt declare no potential conflict of interest.

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Supplementary Information accompanies the paper on the Oncogene website

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Cutrupi, S., Reineri, S., Panetto, A. et al. Targeting of the adaptor protein Tab2 as a novel approach to revert tamoxifen resistance in breast cancer cells. Oncogene 31, 4353–4361 (2012). https://doi.org/10.1038/onc.2011.627

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