Abstract
BackgroundEarly analyses of human breast cancer identified high expression of the insulin-like growth factor type 1 receptor (IGF-1R) correlated with hormone receptor positive breast cancer and associated with a favorable prognosis, whereas low expression of IGF-1R correlated with triple negative breast cancer (TNBC). We previously demonstrated that the IGF-1R acts as a tumor and metastasis suppressor in the Wnt1 mouse model of TNBC. The mechanisms for how reduced IGF-1R contributes to TNBC phenotypes is unknown.MethodsWe analyzed the METABRIC dataset to further stratify IGF-1R expression with patient survival and specific parameters of TNBC. To investigate molecular events associated with the loss of IGF-1R function in breast tumor cells, we inhibited IGF-1R in human cell lines using an IGF-1R blocking antibody and analyzed MMTV-Wnt1-mediated mouse tumors with reduced IGF-1R function through expression of a dominant-negative transgene.ResultsOur analysis of the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) dataset revealed association between low IGF-1R and reduced overall patient survival. IGF-1R expression was inversely correlated with patient survival even within hormone receptor-positive breast cancers, indicating reduced overall patient survival with low IGF-1R was not due simply to low IGF-1R expression within TNBCs. Inhibiting IGF-1R in either mouse or human tumor epithelial cells increased reactive oxygen species (ROS) production and activation of the endoplasmic reticulum stress response. IGF-1R inhibition in tumor epithelial cells elevated interleukin (IL)-6 and C-C motif chemokine ligand 2 (CCL2) expression, which was reversed by ROS scavenging. Moreover, the Wnt1/dnIGF-1R primary tumors displayed a tumor-promoting immune phenotype. The increased CCL2 promoted an influx of CD11b+ monocytes into the primary tumor that also had increased matrix metalloproteinase (MMP)-2, MMP-3, and MMP-9 expression. Increased MMP activity in the tumor stroma was associated with enhanced matrix remodeling and collagen deposition. Further analysis of the METABRIC dataset revealed an increase in IL-6, CCL2, and MMP-9 expression in patients with low IGF-1R, consistent with our mouse tumor model and data in human breast cancer cell lines.ConclusionsOur data support the hypothesis that reduction of IGF-1R function increases cellular stress and cytokine production to promote an aggressive tumor microenvironment through infiltration of immune cells and matrix remodeling.
Highlights
Analyses of human breast cancer identified high expression of the insulin-like growth factor type 1 receptor (IGF-1R) correlated with hormone receptor positive breast cancer and associated with a favorable prognosis, whereas low expression of IGF-1R correlated with triple negative breast cancer (TNBC)
We demonstrate that attenuated IGF-1R signaling in the MMTV-Wnt1 mouse mammary tumor model and in human breast cancer cell lines increases tumor epithelial cellular stress, resulting in upregulation of cytokine production
Low IGF-1R expression is associated with triple-negative, basal-like breast cancer and reduced overall survival Recent analysis of the Cancer Genome Atlas (TCGA) database for IGF-1R expression demonstrated IGF-1R expression levels are reduced in TNBC [15]
Summary
Analyses of human breast cancer identified high expression of the insulin-like growth factor type 1 receptor (IGF-1R) correlated with hormone receptor positive breast cancer and associated with a favorable prognosis, whereas low expression of IGF-1R correlated with triple negative breast cancer (TNBC). Numerous studies have further confirmed cross-talk between the ER and IGF-1R in breast cancer (for review, see [7]) Consistent with these data, loss of IGF-1R has been associated with breast tumor progression into a more undifferentiated phenotype [8], suggesting that IGF-1R is involved in tumor suppression. The usefulness of disrupting IGF-1R signaling in clinical trials has been less than promising and, in some cases, inhibiting the pathway has led to worse outcomes [11, 12]. These diverse results support the possibility that the IGF-1R has a dual function as both a tumor suppressor and an oncogene
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