title: Advanced glycation endproducts increase proliferation, migration and invasion of the breast cancer cell line MDA-MB-231.
abstract: Diabetic patients have increased likelihood of developing breast cancer. Advanced glycation endproducts (AGEs) underlie the pathogenesis of diabetic complications but their impact on breast cancer cells is not understood. This study aims to determine the effects of methylglyoxal-derived bovine serum albumin AGEs (MG-BSA-AGEs) on the invasive MDA-MB-231 breast cancer cell line. By performing cell counting, using wound-healing assay, invasion assay and zymography analysis, we found that MG-BSA-AGEs increased MDA-MB-231 cell proliferation, migration and invasion through Matrigel™ associated with an enhancement of matrix metalloproteinase (MMP)-9 activities, in a dose-dependent manner. Using Western blot and flow cytometry analyses, we demonstrated that MG-BSA-AGEs increased expression of the receptor for AGEs (RAGE) and phosphorylation of key signaling protein extracellular signal-regulated kinase (ERK)-1/2. Furthermore, in MG-BSA-AGE-treated cells, phospho-protein micro-array analysis revealed enhancement of phosphorylation of the ribosomal protein 70 serine S6 kinase beta 1 (p70S6K1), which is known to be involved in protein synthesis, the signal transducer and activator of transcription (STAT)-3 and the mitogen-activated protein kinase (MAPK) p38, which are involved in cell survival. Blockade of MG-BSA-AGE/RAGE interactions using a neutralizing anti-RAGE antibody inhibited MG-BSA-AGE-induced MDA-MB-231 cell processes, including the activation of signaling pathways. Throughout the study, non-modified BSA had a negligible effect. In conclusion, AGEs might contribute to breast cancer development and progression partially through the regulation of MMP-9 activity and RAGE signal activation. The up-regulation of RAGE and the concomitant increased phosphorylation of p70S6K1 induced by AGEs may represent promising targets for drug therapy to treat diabetic patients with breast cancer.
authors.affiliation: School of Healthcare Science, Manchester Metropolitan University, Manchester M1 5GD, United Kingdom.
authors.forename: Hana
authors.initials: H
authors.lastname: Sharaf
authors.affiliation: King Abdullah International Medical Research Center, Medical Genomics Research Department, National Guard Health Affairs, Riyadh 11426, Saudi Arabia.
authors.forename: Sabine
authors.initials: S
authors.lastname: Matou-Nasri
authors.affiliation: School of Healthcare Science, Manchester Metropolitan University, Manchester M1 5GD, United Kingdom.
authors.forename: Qiuyu
authors.initials: Q
authors.lastname: Wang
authors.affiliation: King Abdullah International Medical Research Center, Medical Genomics Research Department, National Guard Health Affairs, Riyadh 11426, Saudi Arabia.
authors.forename: Zaki
authors.initials: Z
authors.lastname: Rabhan
authors.affiliation: King Abdullah International Medical Research Center, Medical Genomics Research Department, National Guard Health Affairs, Riyadh 11426, Saudi Arabia.
authors.forename: Hamad
authors.initials: H
authors.lastname: Al-Eidi
authors.affiliation: King Abdullah International Medical Research Center, Medical Genomics Research Department, National Guard Health Affairs, Riyadh 11426, Saudi Arabia.
authors.forename: Abdulkareem
authors.initials: A
authors.lastname: Al Abdulrahman
authors.affiliation: School of Healthcare Science, Manchester Metropolitan University, Manchester M1 5GD, United Kingdom. Electronic address: N.Ahmed@mmu.ac.uk.
authors.forename: Nessar
authors.initials: N
authors.lastname: Ahmed
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D002417:Cattle; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D048049:Extracellular Signal-Regulated MAP Kinases; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D006801:Humans; D020935:MAP Kinase Signaling System; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins; D010766:Phosphorylation; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000378:metabolism; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D012269:Ribosomal Proteins / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D017127:Glycation End Products, Advanced; D009363:Neoplasm Proteins; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D012269:Ribosomal Proteins; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D048049:Extracellular Signal-Regulated MAP Kinases; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9
keywords: Advanced glycation endproduct; Breast cancer; Diabetes; Methylglyoxal; Signaling pathway