Abstract P4-04-01: A paradigm shift for insulin-like growth factor-1 receptor function in triple negative breast cancers
Authors: Obr AE , Wood TL 
Published: March 2017

Abstract
Loss of insulin growth factor (IGF) signaling in the mammary gland at puberty leads to delayed elongation and defects in terminal end bud (TEB) proliferation. Moreover, IGF signaling is essential for epithelial mesenchymal interactions in mammary bud morphogenesis. 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 metastasis1. Recent analyses of TCGA human datasets support the relevance of our model in human triple negative breast cancers (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), Nanog, Slug, 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 and interleukin-1 in the bigenic tumors suggesting 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 both IL-6 and Slug expression suggesting the tumor cells activate EMT and a pro-tumorigenic microenvironment in response to decreased IGF-1R. Taken together, our data suggest IGF-1R acts as a negative regulator of mediators that promote invasion and metastasis in TNBCs.
References:
1. Rota, L.M., et al., IGF1R inhibition in mammary epithelia promotes canonical Wnt signaling and Wnt1-driven tumors. Cancer Res, 2014. 74(19): p. 5668-79.Loss of insulin growth factor (IGF) signaling in the mammary gland at puberty leads to delayed elongation and defects in terminal end bud (TEB) proliferation. Moreover, IGF signaling is essential for epithelial mesenchymal interactions in mammary bud morphogenesis. 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 metastasis1. Recent analyses of TCGA human datasets support the relevance of our model in human triple negative breast cancers (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), Nanog, Slug, 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 and interleukin-1 in the bigenic tumors suggesting 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 both IL-6 and Slug expression suggesting the tumor cells activate EMT and a pro-tumorigenic microenvironment in response to decreased IGF-1R. Taken together, our data suggest IGF-1R acts as a negative regulator of mediators that promote invasion and metastasis in TNBCs.
References:
1. Rota, L.M., et al., IGF1R inhibition in mammary epithelia promotes canonical Wnt signaling and Wnt1-driven tumors. Cancer Res, 2014. 74(19): p. 5668-79.
Citation Format: Obr AE, Wood TL. A paradigm shift for insulin-like growth factor-1 receptor function in triple negative breast cancers [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-04-01.