Abstract 3617: A paradigm shift for insulin-like growth factor 1 receptor function in triple negative breast cancers

Abstract

Abstract Signaling through the insulin-like growth factor type 1 receptor (IGF-1R) is complex in breast cancers. Early studies reported that expression of the IGF-1R correlated with estrogen receptor (ER) expression and predicted a favorable phenotype. Moreover, loss of IGF-1R has been associated with breast tumor progression into a more undifferentiated phenotype. We have generated and characterized a mouse line containing both MMTV-Wnt1 and MMTV-dnIGF-1R (kinase dead-IGF-1R) transgenes (referred to subsequently as bigenic mice) that leads to increased mammary tumor initiation and metastasis. These data support the hypothesis that the IGF-1R functions in suppressing metastasis in certain contexts and subtypes of triple negative breast cancers (TNBCs). Recent analyses of TCGA human datasets support the relevance of our model in human TNBCs that have reduced IGF-1R expression and increased expression of Wnt1 and the Frizzled co-receptor Lrp6. We have identified alterations in a number of target genes that potentially regulate metastasis in the bigenic primary tumors including increases in interleukin-6 (IL-6), Slug, Vimentin, Zeb 1/2 and decreases in E-cadherin expression as assessed by Qiagen specific qPCR and single gene qPCR. Furthermore, a subset of anti-inflammatory chemokines and cytokines were assessed by a targeted qPCR array revealing increases in interleukin-4, interleukin-10, and C-C motif chemokine ligand-2 and decreases in tumor necrosis factor-alpha in the bigenic tumors indicating a tumor associated macrophage phenotype. By flow cytometry analysis, the ratio of CD4+ T cells to CD8+ T cells is increased in the bigenic tumors suggesting a tumor promoting immune microenvironment. However, increased expression of IL-6 in the bigenic tumors is specific to the luminal tumor cells, and inhibition of IGF-1R in the MCF7 human breast cancer cell line results in increases in IL-6, Slug, and Zeb 1/2 expression suggesting the tumor cells activate EMT and a pro-tumorigenic microenvironment in response to decreased IGF-1R. Moreover, inhibition of IGF-1R in human breast cancer cells and MMTV-Wnt1 mouse tumor cells results in increased cell motility and invasion as assessed by the xCELLigence motility assay. Taken together, our data support the hypothesis that IGF-1R acts as a negative regulator of mediators that promote migration, invasion, and metastasis in TNBCs. Citation Format: Alison Obr, Sushil Kumar, Raymond Birge, Teresa Wood. A paradigm shift for insulin-like growth factor 1 receptor function in triple negative breast cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3617. doi:10.1158/1538-7445.AM2017-3617