Abstract 1845: ADAM10: A new player in breast cancer progression

Abstract

Abstract Background: The ADAMs are a family of proteases, best known for their role in releasing the extracellular domain of transmembrane proteins. One of the ADAMs, i.e., ADAM10, is involved in the activation of 2 important signaling systems controlling cell growth, invasion and metastasis, i.e. the EGFR and NOTCH signaling systems. Because of its ability to activate both EGFR and NOTCH, ADAM10 is likely to play a role in cancer formation or progression. The aim of this study was therefore to investigate the role of ADAM10 in breast cancer and test its therapeutic potential, especially in patients with the triple-negative form of this disease. Materials and Methods: ADAM10 mRNA expression was examined in a pooled collection of publically available databases (n ∼ 4000). ADAM10 protein was examined in a cohort of 120 breast tumor extracts by ELISA. In addition, ADAM10 expression was decreased by RNAi and the effects of this on cell proliferation, invasion and migration were determined. Using the novel ADAM10 inhibitor GI254023X (GSK), we examined the effect of ADAM10 inhibition on a panel of 13 breast cancer cell lines. Results: Using the pooled collection of databases, ADAM10 mRNA was found to be significantly elevated in HER2+ breast cancer compared to other subtypes (p < 0.0001). High ADAM10 mRNA expression was also observed in basal like breast cancer and was associated with poorer overall survival in this subgroup (p = 0.0196). In a cohort of 120 breast tumor extracts, ADAM10 protein was found to be significantly higher in ER-negative compared to ER-positive tumors (p = 0.005), in high grade versus low grade tumors (p < 0.0001), and in younger than older women (p = 0.018). Downregulation of ADAM10 in MDA-MB-231 breast cancer cells resulted in a significant reduction in invasion (p = 0.0006) and cellular migration (p = 0.0002). Treatment of 13 breast cancer cell lines with GI254023X resulted in variable growth inhibition (from 0 to 52%). Furthermore, GI254023X significantly decreased invasion in the MDA-MB-231 cell line (p = 0.001). Conclusions: Our findings of a correlation between ADAM10 and features of aggressive disease and the fact that its downregulation/inhibition decreased growth, invasion and migration suggests that this ADAM10 protease is involved in the progression of breast cancer. Inhibition of ADAM10 with GI254023X may be a new treatment for breast cancer. Acknowledgements: The authors thank SFI and the Molecular Therapeutics for Cancer Ireland (SRC award, 08/SRC/B1410 to MTCI) for funding this work. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1845. doi:1538-7445.AM2012-1845