title: Combined genomic and phenotype screening reveals secretory factor SPINK1 as an invasion and survival factor associated with patient prognosis in breast cancer.
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.
authors.affiliation: Cancer Biology and Pharmacology, Genome Institute of Singapore.
authors.forename: Wendy Weijia
authors.initials: WW
authors.lastname: Soon
authors.forename: Lance David
authors.initials: LD
authors.lastname: Miller
authors.forename: Michael A
authors.initials: MA
authors.lastname: Black
authors.forename: Cyril
authors.initials: C
authors.lastname: Dalmasso
authors.forename: Xiu Bin
authors.initials: XB
authors.lastname: Chan
authors.forename: Brendan
authors.initials: B
authors.lastname: Pang
authors.forename: Chee Wee
authors.initials: CW
authors.lastname: Ong
authors.forename: Manuel
authors.initials: M
authors.lastname: Salto-Tellez
authors.forename: Kartiki V
authors.initials: KV
authors.lastname: Desai
authors.forename: Edison T
authors.initials: ET
authors.lastname: Liu
mesh_terms: D017209:Apoptosis; D001943:Breast Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D002352:Carrier Proteins / Q000032:analysis / Q000037:antagonists & inhibitors / Q000235:genetics*; D005260:Female; D005820:Genetic Testing; D006801:Humans; D007150:Immunohistochemistry; D009361:Neoplasm Invasiveness / Q000235:genetics* / Q000473:pathology*; D011379:Prognosis; D011960:Receptors, Estrogen / Q000032:analysis; D016019:Survival Analysis; D014359:Trypsin Inhibitor, Kazal Pancreatic
chemical_list: D002352:Carrier Proteins; D011960:Receptors, Estrogen; C486642:SPINK1 protein, human; C010140:estrophilin; D014359:Trypsin Inhibitor, Kazal Pancreatic