Abstract
BackgroundInsulin like growth factor binding proteins modulate the mitogenic and pro survival effects of IGF. Elevated expression of IGFBP2 is associated with progression of tumors that include prostate, ovarian, glioma among others. Though implicated in the progression of breast cancer, the molecular mechanisms involved in IGFBP2 actions are not well defined. This study investigates the molecular targets and biological pathways targeted by IGFBP2 in breast cancer.MethodsTranscriptome analysis of breast tumor cells (BT474) with stable knockdown of IGFBP2 and breast tumors having differential expression of IGFBP2 by immunohistochemistry was performed using microarray. Differential gene expression was established using R-Bioconductor package. For validation, gene expression was determined by qPCR. Inhibitors of IGF1R and integrin pathway were utilized to study the mechanism of regulation of β-catenin. Immunohistochemical and immunocytochemical staining was performed on breast tumors and experimental cells, respectively for β-catenin and IGFBP2 expression.ResultsKnockdown of IGFBP2 resulted in differential expression of 2067 up regulated and 2002 down regulated genes in breast cancer cells. Down regulated genes principally belong to cell cycle, DNA replication, repair, p53 signaling, oxidative phosphorylation, Wnt signaling. Whole genome expression analysis of breast tumors with or without IGFBP2 expression indicated changes in genes belonging to Focal adhesion, Map kinase and Wnt signaling pathways. Interestingly, IGFBP2 knockdown clones showed reduced expression of β- catenin compared to control cells which was restored upon IGFBP2 re-expression. The regulation of β-catenin by IGFBP2 was found to be IGF1R and integrin pathway dependent. Furthermore, IGFBP2 and β-catenin are co-ordinately overexpressed in breast tumors and correlate with lymph node metastasis.ConclusionThis study highlights regulation of β-catenin by IGFBP2 in breast cancer cells and most importantly, combined expression of IGFBP2 and β-catenin is associated with lymph node metastasis of breast tumors.
Highlights
Insulin like growth factor binding proteins modulate the mitogenic and pro survival effects of IGF
Insulin like growth factor binding protein 2 (IGFBP2) perturbation by shRNA alters gene expression profile in breast cancer cells In view of the pro-tumorigenic actions of IGFBP2 reported in several cancers including breast tumors, we decided to delineate the molecular mechanism of IGFBP2 actions in breast cancers
Differential expression of genes between tumors staining positive or negative for IGFBP2 In order to determine, whether expression of IGFBP2 regulated genes as revealed by IGFBP2 perturbation is altered in tumors, we studied the gene expression patterns in tumors based on IGFBP2 expression
Summary
Insulin like growth factor binding proteins modulate the mitogenic and pro survival effects of IGF. Elevated expression of IGFBP2 is associated with progression of tumors that include prostate, ovarian, glioma among others. Though implicated in the progression of breast cancer, the molecular mechanisms involved in IGFBP2 actions are not well defined. Elevated expression of IGFBP2 has been observed in multiple malignancies, including Glioblastoma multiforme [2,3,4], ovarian [5,6], pancreatic [7], gastric [8], prostate [9], colon [10], breast [11,12], leukemia [13] and thyroid cancer [14]. Pro proliferative action of IGFBP2 has been reported in prostate, ovarian and colon cancer cells and nontransformed rat osteoblasts [19,21,22,23,24]. Mechanisms that govern IGFBP2 actions in breast cancers are poorly understood
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
