Deregulation of IGF-binding proteins -2 and -5 contributes to the development of endocrine resistant breast cancer in vitro

Yousef Hawsawi, Matthew P Humphries, Alexander Wright, Angelene Berwick, Mike Shires, Hanaa Al-Kharobi, Reem El-Gendy, Maria Jove, Chris Twelves, Valerie Speirs, James Beattie

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10 Citations (Scopus)

Abstract

Tamoxifen (TAM) remains the adjuvant therapy of choice for pre-menopausal women with ERα-positive breast cancer. Resistance and recurrence remain, however, a major challenge with many women relapsing and subsequently dying. The insulin-like growth factor (IGF) axis is involved in breast cancer pathogenesis and progression to endocrine resistant disease, but there is very little data on the expression and potential role of IGF-binding proteins (IGFBP) during acquisition of the resistant phenotype. The aim of this study was to determine the expression and functional role of IGFBP-2 and -5 in the development of TAM resistance (TamR) in vitro and to test retrospectively whether they were predictive of resistance in a tissue microarray of 77 women with primary breast cancers who relapsed on/after endocrine therapy and 193 who did not with long term follow up. Reciprocal expression of IGFBP-2 and IGFBP-5 was observed at both mRNA and protein level in TamR cells. IGFBP-2 expression was increased by 10-fold while IGFBP-5 was decreased by 100-fold, compared to TAM-sensitive control cells. shRNA-mediated silencing of IGFBP-2 in TamR cells restored TAM sensitivity suggesting a causal role for this gene in TamR. While silencing of IGFBP-5 in control cells had no effect on TAM sensitivity, it significantly increased the migratory capacity of these cells. Quantitative image analysis of immunohistochemical data failed, however, to demonstrate an effect of IGFBP2 expression in endocrine-relapsed patients. Likewise, IGFBP-2 and IGFBP-5 expression failed to show any significant associations with survival either in patients relapsing or those not relapsing on/after endocrine therapy. By contrast, in silico mining of a separate published dataset showed that in patients who received endocrine treatment, loss of expression of IGBP-5 was significantly associated with worse survival. Overall these data suggest that co-ordinated and reciprocal alteration in IGFBP-2 and -5 expression may play a role in the acquisition of endocrine resistance.

Original languageEnglish
Pages (from-to)32129-32143
Number of pages15
JournalOncotarget
Volume7
Issue number22
DOIs
Publication statusPublished - 1 Apr 2016

Keywords

  • Antineoplastic Agents, Hormonal
  • Breast Neoplasms
  • Cell Movement
  • Cell Proliferation
  • Chemotherapy, Adjuvant
  • Drug Resistance, Neoplasm
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Insulin-Like Growth Factor Binding Protein 2
  • Insulin-Like Growth Factor Binding Protein 5
  • Kaplan-Meier Estimate
  • MCF-7 Cells
  • Neoplasm Invasiveness
  • Neoplasm Recurrence, Local
  • RNA Interference
  • Risk Assessment
  • Risk Factors
  • Signal Transduction
  • Tamoxifen
  • Time Factors
  • Transfection
  • Treatment Outcome
  • Journal Article

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  • Cite this

    Hawsawi, Y., Humphries, M. P., Wright, A., Berwick, A., Shires, M., Al-Kharobi, H., El-Gendy, R., Jove, M., Twelves, C., Speirs, V., & Beattie, J. (2016). Deregulation of IGF-binding proteins -2 and -5 contributes to the development of endocrine resistant breast cancer in vitro. Oncotarget, 7(22), 32129-32143. https://doi.org/10.18632/oncotarget.8534