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.
Highlights
Development of resistance to anti-oestrogen therapies in patients with ER+ breast cancer (BC) represents a major therapeutic challenge
Changes in IGF-binding proteins (IGFBP)-2 and -5 mRNA concentrations were reflected in protein concentrations in wt and TAM resistance (TamR) cell conditioned medium (CM) as determined by Enzyme-linked immunosorbent assay (ELISA) (Figure 2A), Western blot (Figure 2B, upper two panels) or insulinlike growth factor (IGF) ligand blot (Figure 2B, lower panel)
In some instances for ligand blot of TamR CM IGFBP-5 was below the detection level for this technique – Figure 2 bottom panel
Summary
Development of resistance to anti-oestrogen therapies in patients with ER+ breast cancer (BC) represents a major therapeutic challenge. This is evident in the eventual failure of adjuvant tamoxifen in a proportion of patients, in the premenopausal setting where it remains the therapy of choice. The insulin-like www.impactjournals.com/oncotarget growth factor (IGF) axis plays an important role in the development of normal mammary gland where, in concert with 17β oestradiol, it regulates the proliferation, differentiation and apoptosis of mammary epithelial cells during pregnancy, lactation and subsequent involution of the gland [2]. In many instances such causal relationships have not been validated and subsequent studies have reported no alterations or even down regulation of IGF-1R expression in TamR cells [7,8,9]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
