Abstract
The fetal isoform A of the insulin receptor (IR-A) is frequently overexpressed in a variety of malignancies including breast cancer. IR overexpression has a recognized role in cancer progression and resistance to anticancer therapies. In particular, IR-A has a peculiar mitogenic potential and is activated not only by insulin but also by IGF-2. Previously, we identified discoidin domain receptor 1 (DDR1) as a new IR-A interacting protein. DDR1, a non-integrin collagen tyrosine kinase receptor, is overexpressed in several malignancies and plays a role in cancer progression and metastasis.We now evaluated whether DDR1 is able to exert a role in breast cancer biology by functionally cross-talking with IR. In MCF-7 human breast cancer cells, IR and DDR1 co-immunoprecipitated and co-localized after insulin or IGF-2 stimulation. In a panel of breast cancer cells, DDR1 knockdown by specific siRNAs markedly inhibited IR downstream signaling as well as proliferation, migration and colony formation in response to insulin and IGF-2. These effects were accompanied by reduction of IR protein and mRNA expression, which involved both transcriptional and post-transcriptional effects. DDR1 overexpression elicited opposite effects. Bioinformatics analysis of public domain databases showed that IR and DDR1 co-expression significantly correlates with several clinically relevant histopathological and molecular features of human breast carcinomas.These findings demonstrate that, in human breast cancer cells, DDR1 regulates IR expression and ligand dependent biological actions. This novel functional crosstalk is likely clinically relevant and may become a new molecular target in breast cancer.
Highlights
Dysregulation of the insulin/IGF signaling (IIGFs), involving the overexpression of receptors for insulin growth factor 1 (IGF-1) and/ or insulin (IGF-1R and insulin receptor (IR)) and/or cognate ligands (IGF-1, insulin growth factor 2 (IGF-2)), has an important role in the early phases of carcinogenesis of breast cancer, and is associated with cancer progression and metastases and resistance to a variety of therapies [1,2,3,4]
In a previous study, aimed at discovering new substrates/mediators of the IGF-2/IR-A pathway, we reported that discoidin domain receptor 1 (DDR1) is found in multiprotein complexes associated with tyrosine-phosphorylated IR in response to IGF-2 and to a lesser extent to insulin [15]
We first evaluated by immunoblot the expression of DDR1 and IR in a panel of human breast cancer cell lines (MCF-7, T47D, ZR-75, BT-474, MDA-MB-157, MDAMB-231, MDA-MB-468)
Summary
Dysregulation of the insulin/IGF signaling (IIGFs), involving the overexpression of receptors for IGF-1 and/ or insulin (IGF-1R and IR) and/or cognate ligands 1, IGF-2), has an important role in the early phases of carcinogenesis of breast cancer, and is associated with cancer progression and metastases and resistance to a variety of therapies [1,2,3,4]. A major mechanism of resistance to anti-IGF-1R drugs involves the IR, which is commonly overexpressed in breast cancer and predominantly expressed as the so called ‘fetal isoform’ (IR-A), which is a bona fide receptor for IGF-2 and proinsulin [11, 12]. The IR-A/IGF-2 autocrine loop plays a key role in many cancer histotypes, including breast cancer [13, 14]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
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.
