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

Christine Mehner, Ann L Oberg, Kimberly R. Kalli, Aziza Nassar, Alexandra Hockla, Devon Pendlebury, Magdalena A. Cichon, Krista M. Goergen, Matthew J. Maurer, Ellen L Goode, Gary Keeney, Aminah Jatoi, Miklós Sahin-Tóth, John A III Copland, Derek C Radisky, Evette S Radisky

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)35737-35754
Number of pages18
JournalOncotarget
Volume6
Issue number34
DOIs
StatePublished - 2015

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Keywords

  • Anoikis
  • EGFR
  • Ovarian cancer
  • Serine protease inhibitor
  • SPINK1

ASJC Scopus subject areas

  • Oncology

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