Deregulation of IGF-binding proteins -2 and -5 contributes to the development of endocrine resistant breast cancer in vitro
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Yousef Hawsawi1,3,4, Matthew P. Humphries3, Alexander Wright3, Angelene Berwick3, Mike Shires3, Hanaa Al-Kharobi1, Reem El-Gendy1, Maria Jove2, Chris Twelves2,3, Valerie Speirs3, James Beattie1
1Department of Oral Biology, St James’s University Hospital, Leeds, UK
2St James’s Institute of Oncology, St James's University Hospital, Leeds, UK
3Leeds Institute of Cancer and Pathology, University of Leeds, UK
4Current address: Department of Breast Medical Oncology, MD Anderson Cancer Centre, University of Texas, Houston, USA
James Beattie, email: [email protected]
Valerie Speirs, email: [email protected]
Keywords: IGF, breast cancer, endocrine resistance
Received: January 26, 2016 Accepted: March 14, 2016 Published: April 01, 2016
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.
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