Serine protease inhibitor Kazal type 1 (SPINK1) drives proliferation and anoikis resistance in a subset of ovarian cancers

Abstract

// Christine Mehner 1 , Ann L. Oberg 2 , Kimberly R. Kalli 3 , Aziza Nassar 4 , Alexandra Hockla 1 , Devon Pendlebury 1 , Magdalena A. Cichon 1 , Krista M. Goergen 2 , Matthew J. Maurer 2 , Ellen L. Goode 5 , Gary L. Keeney 6 , Aminah Jatoi 3 , Miklós Sahin-Tóth 7 , John A. Copland 1 , Derek C. Radisky 1 and Evette S. Radisky 1 1 Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, USA 2 Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, MN , USA 3 Department of Medical Oncology, Mayo Clinic, Rochester, MN, USA 4 Department of Laboratory Medicine and Pathology, Mayo Clinic, Jacksonville, FL, USA 5 Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA 6 Division of Anatomic Pathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA 7 Department of Molecular and Cell Biology, Boston University Henry M. Goldman School of Dental Medicine, Boston, MA, USA Correspondence to: Evette S. Radisky, email: // Keywords : SPINK1, ovarian cancer, serine protease inhibitor, EGFR, anoikis Received : July 07, 2015 Accepted : September 14, 2015 Published : September 30, 2015 Abstract Ovarian cancer represents the most lethal tumor type among malignancies of the female reproductive system. Overall survival rates remain low. In this study, we identify the serine protease inhibitor Kazal type 1 (SPINK1) as a potential therapeutic target for a subset of ovarian cancers. We show that SPINK1 drives ovarian cancer cell proliferation through activation of epidermal growth factor receptor (EGFR) signaling, and that SPINK1 promotes resistance to anoikis through a distinct mechanism involving protease inhibition. In analyses of ovarian tumor specimens from a Mayo Clinic cohort of 490 patients, we further find that SPINK1 immunostaining represents an independent prognostic factor for poor survival, with the strongest association in patients with nonserous histological tumor subtypes (endometrioid, clear cell, and mucinous). This study provides novel insight into the fundamental processes underlying ovarian cancer progression, and also suggests new avenues for development of molecularly targeted therapies.