title: Serine protease inhibitor Kazal type 1 (SPINK1) drives proliferation and anoikis resistance in a subset of ovarian cancers.
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.
authors.affiliation: Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: Christine
authors.initials: C
authors.lastname: Mehner
authors.affiliation: Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
authors.forename: Ann L
authors.initials: AL
authors.lastname: Oberg
authors.affiliation: Department of Medical Oncology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Kimberly R
authors.initials: KR
authors.lastname: Kalli
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: Aziza
authors.initials: A
authors.lastname: Nassar
authors.affiliation: Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Hockla
authors.affiliation: Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: Devon
authors.initials: D
authors.lastname: Pendlebury
authors.affiliation: Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: Magdalena A
authors.initials: MA
authors.lastname: Cichon
authors.affiliation: Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
authors.forename: Krista M
authors.initials: KM
authors.lastname: Goergen
authors.affiliation: Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Maurer
authors.affiliation: Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
authors.forename: Ellen L
authors.initials: EL
authors.lastname: Goode
authors.affiliation: Division of Anatomic Pathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Gary L
authors.initials: GL
authors.lastname: Keeney
authors.affiliation: Department of Medical Oncology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Aminah
authors.initials: A
authors.lastname: Jatoi
authors.affiliation: Department of Molecular and Cell Biology, Boston University Henry M. Goldman School of Dental Medicine, Boston, MA, USA.
authors.forename: Miklós
authors.initials: M
authors.lastname: Sahin-Tóth
authors.affiliation: Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: John A
authors.initials: JA
authors.lastname: Copland
authors.affiliation: Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: Derek C
authors.initials: DC
authors.lastname: Radisky
authors.affiliation: Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: Evette S
authors.initials: ES
authors.lastname: Radisky
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D023102:Anoikis / Q000235:genetics; D014408:Biomarkers, Tumor / Q000378:metabolism*; D018269:Carcinoma, Endometrioid / Q000175:diagnosis* / Q000401:mortality; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D006801:Humans; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D010051:Ovarian Neoplasms / Q000175:diagnosis* / Q000401:mortality; D011379:Prognosis; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D016019:Survival Analysis; D014359:Trypsin Inhibitor, Kazal Pancreatic; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; D002352:Carrier Proteins; D034741:RNA, Small Interfering; C486642:SPINK1 protein, human; D014359:Trypsin Inhibitor, Kazal Pancreatic; C512478:EGFR protein, human; D066246:ErbB Receptors
keywords: EGFR; SPINK1; anoikis; ovarian cancer; serine protease inhibitor