Abstract LB-204: Oncogenic Ras signaling requires serine protease hepsin to induce invasive breast cancer phenotype

Abstract

Abstract Invasive cancer growth occurs when epithelial tumor cells individually or collectively detach from the primary tumor and migrate into the adjacent healthy tissue. This process starts a gradual tumor progression that may lead to life-threatening metastatic disease. Hepsin is a type II transmembrane serine protease that is frequently overexpressed in breast, prostate, and other epithelial cancers. It promotes tumor progression through activating growth factors and disrupting cell-cell and cell-basement membrane (BM) junctions. Although hepsin participates in pericellular cancer degradome, the oncogenic upstream mechanisms that activate hepsin in cancer are not well known. We found that oncogenic Ras proteins by activating MAPK pathway signaling alter the ratio of hepsin and HAI-1 to increase the proteolytic activity of hepsin. In 3D epithelial culture models of Ras-driven cancer, depletion of hepsin by shRNA restored desmosomes, BM defects, and glandular morphology but not the apical polarity. Mechanistically, Ras-MAPK pathway affected hepsin/HAI-1 via two distinct downstream pathways: Hepsin protein was stabilized via Ras-induced and heat shock transcription factor-1-mediated stress pathway, whereas HAI-1 was down-regulated by Ras via tumor suppressor LKB1 and PI3K-dependent pathways. Altogether, the results suggest that abnormal activation of Ras-MAPK pathway elevates hepsin activity to execute early steps of breast cancer invasion. Citation Format: Shishir Mani Pant, Topi Tervonen, Denis Belitskin, Johanna Englund, Emmy Verschuren, Panu Kovanen, Juha Klefstrom. Oncogenic Ras signaling requires serine protease hepsin to induce invasive breast cancer phenotype [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-204.