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Ski-related novel protein N (SnoN), a Negative Controller of Transforming Growth Factor-ß Signaling, Is a Prognostic Marker in Estrogen Receptor-positive Breast Carcinomas¹ ,^,2

Haartman Institute [F. Z., A. R., P. H., Ma. L.] and Molecular Cancer Biology Program [F. Z., A. R., H. J., Ma. L.], Biomedicum Helsinki, University of Helsinki and Helsinki University Central Hospital [Mi. L., A. R., P. H., J. L., H. J.], FIN-00014 Helsinki, and Institute of Medical Technology, University of Tampere, FIN-33014 Tampere [J. I.], Finland

Transforming growth factor (TGF)-ß arrests the growth of breast epithelial cells, whereas breast cancer cells are highly resistant to its growth restrictive properties. To define causes for the defect in TGF-ß action, we present here the first in vivo analysis of Ski-related novel protein N (SnoN), a negative regulator of TGF-ß signaling, in human breast carcinomas. SnoN expression was analyzed by immunohistochemistry in a tissue microarray of 1122 breast carcinomas and 10 reduction mammoplasties. In the normal breast, SnoN was located predominantly in nuclei of large duct epithelial cells and the cytoplasm of terminal duct epithelial cells. Breast cancers displayed variances in both SnoN expression levels and subcellular localizations. High levels of cytoplasmic SnoN were more often observed in tumors of ductal histological type and associated with adverse prognostic features, such as lack of hormone receptors; high levels of p53, Ki-67, and cyclooxygenase-2; and amplifications of HER-2. High levels of nuclear SnoN were associated with lobular histology and favorable features, including presence of hormone receptors, low expression of p53 and Ki-67, and lack of HER-2 amplifications. Reduced expression of SnoN significantly correlated with longer distant disease-free survival in estrogen receptor-positive patients (P = 0.0027, relative risk = 3.27; 95% confidence interval = 1.44–7.41). The results suggest that the subcellular localization of SnoN may have clinical significance and that reduced expression of SnoN is associated with favorable outcome in estrogen receptor-positive breast cancer.

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