Abstract 889: Growth differentiation factor 15 causes increased invasiveness and EMT in HER2-overexpressing breast cancer via activation of p38 MAPK.

Abstract

Abstract HER2 overexpression in breast cancer is frequently associated with aggressive and metastatic disease. De novo and acquired resistance to the first line therapy trastuzumab are major clinical issues that need to be addressed. We recently reported that the cytokine growth differentiation factor 15 (GDF15) is overexpressed in HER2-overexpressing breast cancer cell lines that have acquired or primary resistance to trastuzumab. GDF15, a distant member of the TGF-beta superfamily, has been associated with increased disease aggression in many malignancies. Our previous study showed that GDF15 activates the TGF-β receptor/src/HER2 signaling pathway, resulting in trastuzumab resistance. We recently observed that overexpression of GDF15 resulted in increased invasion in ovarian and breast cancer cells. In the present study, we investigate the molecular mechanisms underlying GDF15-induced invasion of HER2-overexpressing breast cancer cells resistant to trastuzumab. We demonstrate that GDF15-mediated invasion of breast cancer cells involves increased p38 MAPK activity. HER2-overexpressing breast cancer cells stably transfected with GDF15 showed EMT, increased cellular invasion, phosphorylation of p38, and increased MMP-2 and MMP-9 transcript expression. Furthermore, pharmacologic or genetic inhibition of p38 MAPK decreased invasion of breast cancer cells and improved response to trastuzumab. Also, knockdown of GDF15 suppressed expression of the p38 target genes MMP-2 and MMP-9. Finally, immunohistochemical analysis of a breast tumor tissue array showed a significant correlation (p=0.0053) between HER2 status and p38 phosphorylation in GDF15-positive breast cancers, as well as significant associations between GDF15 and MMP-2 (p=0.0027) and phosphorylated p38 and MMP-2 (0.0066) in HER2-overexpressing breast cancers. Our findings indicate a novel role for GDF15-stimulated p38 signaling in trastuzumab resistance, invasion, and tumor growth of HER2-overexpressing breast cancers. Citation Format: Jayashree P. Joshi, Zhengjia Chen, Rita Nahta. Growth differentiation factor 15 causes increased invasiveness and EMT in HER2-overexpressing breast cancer via activation of p38 MAPK. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 889. doi:10.1158/1538-7445.AM2013-889