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Title: Combined genomic and phenotype screening reveals secretory factor SPINK1 as an invasion and survival factor associated with patient prognosis in breast cancer
Authors: Soon, W.W.
Miller, L.D.
Black, M.A.
Dalmasso, C.
Chan, X.B.
Pang, B.
Ong, C.W. 
Salto-Tellez, M. 
Desai, K.V.
Liu, E.T.
Keywords: Breast cancer
Cancer therapy
Distant metastasis-free survival
Expression microarrays
Issue Date: Aug-2011
Citation: Soon, W.W., Miller, L.D., Black, M.A., Dalmasso, C., Chan, X.B., Pang, B., Ong, C.W., Salto-Tellez, M., Desai, K.V., Liu, E.T. (2011-08). Combined genomic and phenotype screening reveals secretory factor SPINK1 as an invasion and survival factor associated with patient prognosis in breast cancer. EMBO Molecular Medicine 3 (8) : 451-464. ScholarBank@NUS Repository.
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. © 2011 EMBO Molecular Medicine.
Source Title: EMBO Molecular Medicine
ISSN: 17574676
DOI: 10.1002/emmm.201100150
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