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.
Highlights
Secretory factors that drive cancer progression are attractive immunotherapeutic targets
Immunohistochemistry showed that Serine protease inhibitor Kazal-type 1 (SPINK1) was absent in normal breast, present in early and advanced tumours, and its expression correlated with poor survival in ERþ tumours
Because SPINK1 effects are abrogated by neutralizing antibodies, we suggest that SPINK1 is a viable potential therapeutic target in breast cancer
Summary
Secretory factors that drive cancer progression are attractive immunotherapeutic targets. Resistance to prevailing drug treatments prompts a need to find novel molecular targets for antibody-based or small molecule-based therapeutics Towards this end, we mined the expression profiles of 760 primary breast cancers from multiple patient cohorts to select genes encoding extracellular proteins, secreted growth factors and cell surface receptors that are consistently associated with poor patient survival for potential therapeutic targets. It has been suggested that SPINK1 induces cellular invasion through pathways such as phosphoinositide 3-kinase (PI3K), Rho-like GTPases and protein kinase C (PKC) This process appears to require its trypsin inhibitory property as a single mutation at the trypsin binding site fails to induce cellular invasion of colon cancer cells (Gouyer et al, 2008). These data suggest that SPINK1 confers some oncogenic properties to cancer cells
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