Importance of different gr owth factors in oestrogen receptor-negative breast cancer

Abstract

The aims of this study were firstly, to investigate the role of growth hormones: insulin-like growth factor (IGF-I), epidermal growth factor (EGF) and heregulin-1 (HRG) on the anchorage-independent survival and migration of oestrogen non-responsive breast cancer cells. Secondly, the effects of inhibition of the type I IGF receptor (IGF-IR), EGF receptor (EGFR) and human epidermal growth factor receptor 2 (HER-2) were studied. Thirdly, the expression of IGF-IR, EGFR, HER-2, TFF1 and TFF3 was assessed in oestrogen receptor-negative breast tumours and involved lymph node metastases, and associations with biomarkers of cell survival and proliferation analysed. IGFs and EGFs contribute to the growth, survival and metastasis of malignant cells and inhibitors of IGF-IR and EGFR are in clinical trials. IGF and EGF signal transduction pathways are proposed to be important in oestrogen non-responsive, HER-2 positive and triple-negative breast cancers. The effects of IGF and EGF on anchorage-independent cell survival and cell migration have not been investigated thoroughly. An in vitro model of anoikis was developed for triple-negative MDA-MB-231, Hs578T and HER-2 positive SK-BR-3 breast cancer cells. For the first time, an anti-anoikis effect of IGF-1 was demonstrated in triple-negative breast cancer cells. The survival effect of IGF-1 was shown to be via activation of the IGF-IR. EGF and HRG were protective against anoikis in oestrogen receptor-negative breast cancer cells. The protective effect of EGF was mediated through EGFR. IGF-1, EGF and HRG demonstrated powerful migratory effects on oestrogen non-responsive breast cancer cells and the inhibition of IGF-IR and EGFR in these cells reduced the cell migration. The combination of IGF-1 and EGF induced more cell migration than either ligand alone. IGF-IR, EGFR and HER-2 were expressed in oestrogen receptor-negative breast primary tumours, and expression of IGF-IR and EGFR was associated with biomarkers of cell survival and proliferation. Expression of TFF3 was detected at higher levels than TFF1 in both in situ and invasive breast tumours and was associated significantly with expression of HER-2 in invasive breast tumours. ii Overall, these results demonstrated the importance of different growth factors alone and in combination in oestrogen non-responsive breast cancer. Further investigation of the potential of targeting the metastatic progression of oestrogen non-responsive breast cancer via the IGF and EGF signal transduction pathways is merited.