title: Binding of anterior gradient 2 and estrogen receptor-α: Dual critical roles in enhancing fulvestrant resistance and IGF-1-induced tumorigenesis of breast cancer.
abstract: Anterior gradient 2 (AGR2), an essential cancer biomarker, has been widely reported to be associated with estrogen receptor (ER) positive breast cancer development. Here, we uncovered the role of cytoplasmic and exogenous AGR2, through interaction with ER-α, in enhancing fulvestrant resistance and IGF-1-induced carcinogenesis respectively. Our present study revealed that the endogenous AGR2 level positively correlates with fulvestrant resistance in MCF-7 and T47D cells. AGR2-knockdown in MCF-7 cells strongly enhances the fulvestrant-induced G1 phase arrest and accelerates the fulvestrant-induced ER-α degradation. Furthermore, intracellular AGR2 exhibits a functional interaction with ER-α. On the other hand, extracellular AGR2 remarkably promotes the IGF-1-induced cell proliferation, migration, cell cycle progression and epithelial-mesenchymal transition. Extracellular AGR2 also enhances IGF-1 downstream signaling. We also showed that ER-α specifically interacts with both extracellular AGR2 and IGF-1 receptor as a potential intermediator. Finally, we revealed that the adjuvant therapy of AGR2 monoclonal antibody enhances the inhibitory effects of fulvestrant and linsitinib toward breast cancer development. Our findings, for the first time, point out the different functions of intra- and extra-cellular AGR2, providing new insights into the development of anti-tumor therapies targeting AGR2.
authors.affiliation: School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China; School of Medicine, University of Pittsburgh, 200 Lothrop Street, Pittsburgh, PA 15213, USA.
authors.forename: Zheqi
authors.initials: Z
authors.lastname: Li
authors.affiliation: School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhu
authors.affiliation: School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Chen
authors.affiliation: School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China.
authors.forename: Lingyun
authors.initials: L
authors.lastname: Hu
authors.affiliation: School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China.
authors.forename: Hema
authors.initials: H
authors.lastname: Negi
authors.affiliation: School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China.
authors.forename: Yeasin
authors.initials: Y
authors.lastname: Ahmed
authors.affiliation: School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China. Electronic address: wuzhenghua@sjtu.edu.cn.
authors.forename: Zhenghua
authors.initials: Z
authors.lastname: Wu
authors.affiliation: School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China; Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, 800 Dongchuan Road, Shanghai 200240, China. Electronic address: daweili@sjtu.edu.cn.
authors.forename: Dawei
authors.initials: D
authors.lastname: Li
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology; D065171:Estrogen Receptor Antagonists / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D005260:Female; D000077267:Fulvestrant; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D061986:MCF-7 Cells; D009088:Mucoproteins; D015513:Oncogene Proteins; D011485:Protein Binding; D011506:Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D059748:Proteolysis; D011719:Pyrazines / Q000494:pharmacology; D034622:RNA Interference; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection
chemical_list: C551528:3-(8-amino-1-(2-phenylquinolin-7-yl)imidazo(1,5-a)pyrazin-3-yl)-1-methylcyclobutanol; C502296:AGR2 protein, human; D000911:Antibodies, Monoclonal; D018931:Antineoplastic Agents, Hormonal; C506487:ESR1 protein, human; D065171:Estrogen Receptor Antagonists; D047628:Estrogen Receptor alpha; C583557:IGF1 protein, human; D007093:Imidazoles; D009088:Mucoproteins; D015513:Oncogene Proteins; D011506:Proteins; D011719:Pyrazines; D000077267:Fulvestrant; D004958:Estradiol; D007334:Insulin-Like Growth Factor I
keywords: Adjuvant chemotherapy; Anterior gradient 2; Estrogen receptor-α; Fulvestrant; Insulin-like growth factor-1