Combined genomic and phenotype screening reveals secretory factor SPINK1 as an invasion and survival factor associated with patient prognosis in breast cancer

Wendy Weijia Soon, Lance David Miller, Michael A Black, Cyril Dalmasso, Xiu Bin Chan, Brendan Pang, Chee Wee Ong, Manuel Salto-Tellez, Kartiki V Desai, Edison T Liu

Research output: Contribution to journalArticlepeer-review

40 Citations (Scopus)

Abstract

Secretory factors that drive cancer progression are attractive immunotherapeutic targets. We used a whole-genome data-mining approach on multiple cohorts of breast tumours annotated for clinical outcomes to discover such factors. We identified Serine protease inhibitor Kazal-type 1 (SPINK1) to be associated with poor survival in estrogen receptor-positive (ER+) cases. Immunohistochemistry showed that SPINK1 was absent in normal breast, present in early and advanced tumours, and its expression correlated with poor survival in ER+ tumours. In ER- cases, the prognostic effect did not reach statistical significance. Forced expression and/or exposure to recombinant SPINK1 induced invasiveness without affecting cell proliferation. However, down-regulation of SPINK1 resulted in cell death. Further, SPINK1 overexpressing cells were resistant to drug-induced apoptosis due to reduced caspase-3 levels and high expression of Bcl2 and phospho-Bcl2 proteins. Intriguingly, these anti-apoptotic effects of SPINK1 were abrogated by mutations of its protease inhibition domain. Thus, SPINK1 affects multiple aggressive properties in breast cancer: survival, invasiveness and chemoresistance. Because SPINK1 effects are abrogated by neutralizing antibodies, we suggest that SPINK1 is a viable potential therapeutic target in breast cancer.
Original languageEnglish
Pages (from-to)451-64
Number of pages14
JournalEMBO Molecular Medicine
Volume3
Issue number8
DOIs
Publication statusPublished - Aug 2011

Bibliographical note

Copyright © 2011 EMBO Molecular Medicine.

Keywords

  • Neoplasm Invasiveness
  • Genetic Testing
  • Apoptosis
  • Carrier Proteins
  • Humans
  • Prognosis
  • Breast Neoplasms
  • Immunohistochemistry
  • Female
  • Survival Analysis
  • Receptors, Estrogen

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