Induction of anterior gradient 2 (AGR2) plays a key role in insulin-like growth factor-1 (IGF-1)-induced breast cancer cell proliferation and migration.

Zheqi Li,Lingyun Hu,Guangwei Gao,Dawei Li,Qi Zhu,Hao Chen,Zhenghua Wu,Suchitra Kamle,Hema Negi

doi:10.1007/s12032-015-0577-z

Abstract

Anterior gradient 2 (AGR2) is a promising anti-tumor target associated with estrogen receptor expression and metastatic progression of breast cancer. Insulin-like growth factor-1 (IGF-1) is another potent factor that stimulates breast cancer progression and mediates anti-estrogen drug resistance. However, the precise mechanism and connections between these two factors in breast cancer drug resistance have not been fully elucidated. Here, for the first time, we decipher that IGF-1 remarkably induces AGR2 in the MCF7 cell line, through an estrogen response element (ERE) between −802 and −808 bp and a leucine zipper transcription factor-binding site located between −972 and −982 bp on the AGR2 promoter. We also found that the ERK1/2 and AKT pathways mediate estrogen receptor-α at the upstream of ERE and that the JNK pathway activates the leucine zipper site through the c-Jun/c-Fos complex. Additionally, our data suggest that knockdown of AGR2 reduces IGF-1-induced cell proliferation, migration and cell cycle progression. Therefore, we report that AGR2 is a key modulator involved in IGF-1-induced breast cancer development. We propose that the identification of the mechanism linking the IGF-1/insulin signal and AGR2 promoter activation is important, because it provides insights into the development of anti-breast cancer drugs.

Highlights

Anterior gradient-2 (AGR2), known as HAG-2, is the human homologue of Xenopus laevis cement gland protein XAG-2 [1] and nAG, which is responsible for limb regeneration in the newt [2]
For the first time, we decipher that Insulin-like growth factor-1 (IGF-1) remarkably induces Anterior gradient 2 (AGR2) in the MCF7 cell line, through an estrogen response element (ERE) between -802 and -808 bp and a leucine zipper transcription factor-binding site located between -972 and -982 bp on the AGR2 promoter
We propose that the IGF1-induced anti-estrogen drug resistance requires AGR2, because AGR2 is involved in the regulation of cell proliferation, migration and cell cycle progression by IGF-1

Summary

Introduction

Anterior gradient-2 (AGR2), known as HAG-2, is the human homologue of Xenopus laevis cement gland protein XAG-2 [1] and nAG, which is responsible for limb regeneration in the newt [2]. AGR2 has been reported to be overexpressed in several human cancers [3], including estrogen receptor (ER)-positive breast cancer. The clinical and prognostic significance of AGR2 has been demonstrated, suggesting its potential as a tumor diagnostic marker [5] and a modulator in breast cancer anti-estrogen drug resistance [6]. AGR2 expression is increased over sevenfold in the presence of estrogen in hormone-dependent breast cancer cells [7]. AGR2 expression was reported to be activated by estradiol, through the binding of ER to the estrogen response elements (ERE) located in the potential transcriptional regulatory region of AGR2 promoter. The ErbB3-binding protein 1 (EBP1)—Foxa signal circuit [10]—was reported as playing a significant role in AGR2 promoter modulation

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