Differential Expression of Insulin‐Like Growth Factor‐1 Receptor in Breast Cancer Subtypes: A Marker of Early Metastasis in HER‐2 Subtype

Abstract

BackgroundInsulin‐like growth factor‐1 receptor (IGF‐1R) is commonly found to be expressed in both normal and malignant breast samples, and was shown to be involved in cell growth, survival as well as resistance to cytotoxic therapies. Recently, it was suggested that IGF‐1R might play a differential role in breast cancer (BC) subtypes with a favorable prognosis in some molecular subtypes and a poor outcome in others. The aim of present study is to investigate the expression levels of IGF‐1R in BC of different molecular subtypes as well as its impact on patients’ clinical outcome.Materials and MethodsIn this study, the expression IGF‐1R was assessed by immunohistochemistry (IHC) in 60 formalin‐fixed paraffin‐embedded BC tissue specimens. In addition, IGF‐1R expression level was measured and compared in 4 BC cell lines (MCF‐7, SKBR‐3, BT‐549 and MDA‐MB‐231) with that of human mammary epithelial cells (HMEpC) by western blot. Moreover, large publicly available databases of BC samples from different BC subtypes were extracted and analyzed.ResultsInterpretation of IHC staining showed IGF‐1R overexpression in 44 out of 60 (73.33%) BC cases (Figure 1). This was confirmed in 389 patients’ samples extracted from TCGA database that revealed higher levels of IGF‐1R mRNA when paralleled with 61 normal samples. Furthermore, IGF‐1R expression showed a significant association with estrogen and progesterone receptors status (p=0.015 and p=0.005 respectively) and its expression was more pronounced in luminal tumors compared to triple negative (TNBC) samples (p=0.002). These results were further confirmed using 1881 BC samples from publicly available GOBO databases (p<0.0001).In confirmation with our patients’ IHC results and the in silico findings, in vitro results portrayed significantly elevated levels of IGF‐1R in BC cell lines when compared to HMEpC cells; IGF‐1R expression was highest in luminal A (MCF7) cell line and least in the ER‐negative (SKBR‐3 and MDA‐MB‐231) cell lines.Investigating the impact of IGF‐1R expression on patients’ outcome using the same 1881 BC samples, IGF‐1R levels showed no significant association with distant metastasis‐free survival (DMFS) in luminal A and luminal B as well as basal subtypes, while its expression in HER‐2 breast cancer subtypes was found to be significantly associated with higher chance of development of distant metastasis (p=0.03) (Figure 2).ConclusionThe selective upregulation of IGF‐1R expression in luminal subtypes may represent a promising approach in targeted therapy. In addition, the association between IGF‐1R and poor patients’ outcome in HER‐2 BC subtype further confirm the previous clinical reports which highlight a role of IGF‐1R in trastuzumab resistance and elaborate the need to target this pathway as a novel mechanism to overcome drug resistance in HER‐2 BC subtype.Support or Funding InformationThis study was funded by the Boehringer Ingelheim‐University of Sharjah award at its fifth round (2017/2018)Figure 1Figure 2