Abstract 4612: In breast cancer cells IGF-I induces upregulation of DDR1 by suppressing miR-199a-5p via the PI3K/Akt pathway

Abstract

Abstract Discoidin Domain Receptor 1 (DDR1) is a collagen receptor tyrosine-kinase that is implicated in tumor progression by contributing to epithelial mesenchymal transition (EMT) and by enhancing tumor cell migration and invasion. We previously demonstrated that, in breast cancer cells, DDR1 functionally cross-talks with IGF-I receptor (IGF-IR), by affecting IGF-IR expression and trafficking. In these cells, DDR1 was able to enhance the stimulatory effects of IGF-I on mitogenesis and invasion suggesting that the DDR1-IGF-IR cross-talk may play a role in cancer progression. Herein, we evaluated whether IGF-I may in turn affect DDR1 expression. Indeed, we demonstrated that in breast cancer cells (MCF-7 and MDA-MB-231), IGF-I was able to upregulate DDR1 protein expression in a time and dose dependent manner. In contrast, DDR1 mRNA levels showed non-significant changes after stimulation with IGF-I. Moreover, we found that DDR1 protein upregulation requires the activation of the PI3K/Akt pathway, while the Erk1/2, the p70/mTOR and the PKC pathways are not involved. Indeed, IGF-I induced DDR1 protein upregulation through a post-trascriptional mechanism involving miR-199a-5p suppression via Akt. We also found that autocrine IGF-II, induced by stable IGF-II cDNA transfection, is also able to elicit significant DDR1 upregulation in breast cancer cells. Similar effects were induced by IGF-II secreted by human cancer associated fibroblasts. Finally, we showed that miR-199a-5p transfection in breast cancer cells, decreased DDR1 expression and affected the response to IGF-I in terms of intracellular signaling through the PI3K/Akt and Erk1/2 pathways, and biological effects such as cell proliferation and migration. These results demonstrate that the protumoral effects of IGF-I include downregulation of miR-199a-5p and consequent upregulation of DDR1 protein. Both these molecules may represent important targets for breast cancers with overactivation of the IGF-IR axis. Citation Format: Chiara Palladino, Roberta Matà, Maria Luisa Nicolosi, Anna Rita Lo Presti, Roberta Malaguarnera, Marco Ragusa, Daniela Sciortino, Andrea Morrione, Marcello Maggiolini, Veronica Vella, Antonino Belfiore. In breast cancer cells IGF-I induces upregulation of DDR1 by suppressing miR-199a-5p via the PI3K/Akt pathway. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4612.