Our previous study demonstrated that high mRNA levels for Seven in Absentia Homolog 2 (SIAH2) correlated with high Estrogen Receptor (ER) mRNA levels and with longer progression-free survival (PFS) after first-line tamoxifen. Others showed high SIAH2 protein levels in ER-negative breast cancer associated with an unfavorable relapse-free survival. In the current study, we investigated SIAH2 protein expression to clarify the discrepancy between protein and mRNA findings and to determine its diagnostic value in breast cancer patients. Tissue microarrays (TMAs) containing core specimens of primary breast tumors were immunohistochemically stained for SIAH2 protein. The TMAs analyzed a cohort of 746 patients with primary breast cancer (PBC) and a cohort of 245 patients with ER-positive metastatic breast cancer (MBC) treated with first-line tamoxifen. SIAH2 staining was scored for intensity and proportion of positive tumor cells and evaluated for its relationship with metastasis-free survival (MFS) and PFS. Multivariate survival analyses included traditional prognostic or predictive factors, respectively. The PBC-cohort had 263 patients with high SIAH2 protein expression and decreased expression of ER protein and mRNA levels (P = 0.005 and P = 0.003, respectively). High SIAH2 levels correlated with significant unfavorable MFS in lymph node negative, ER-positive breast cancer patients. The MBC-cohort had 86 patients with increased SIAH2 protein expression. High SIAH2 expression was associated with an unfavorable PFS after first-line tamoxifen in multivariate analyses (HR = 1.45; 95% CI, 1.07-1.96; P = 0.015). In conclusion, SIAH2 protein expression is especially observed in ER-negative tumors. Its prognostic value in breast cancer does not add to current prognostic markers. The proportion of SIAH2-positive cells can be used as biomarker to predict tamoxifen treatment failure in MBC patients.

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Keywords Breast cancer, Endocrine therapy resistance, Immunohistochemistry, Seven-in-absentia-homolog 2, Tissue microarray
Sponsor This work was supported by the European Framework Program (FP7-CAREMORE to AT, FP7-DNA damage response to AT-J), the Eu- ropean Research Council (ERC-Advanced to ML and RF), Cancer Genomics Netherlands to JM, Top Institute Pharma (T3-108, T3-502 to EB and MJ) and KNAW Van Walree (KvdW).
Persistent URL dx.doi.org/10.1158/1538-7445.SABCS15-P5-08-51, hdl.handle.net/1765/96698
Journal American Journal of Cancer Research
Grant This work was funded by the European Commission 7th Framework Programme; grant id fp7/601760 - Cancer Responsiveness Monitoring based on Resistance mutations in CTCs (CAREMORE), This work was funded by the European Commission 7th Framework Programme; grant id erc/206281 - DNA damage response and genome stability: The role of ATM, ATR and the Mre11 complex (AAMDDR)
van der Willik, K.D, Timmermans, A.M, van Deurzen, C.H.M, Look, M.P, Reijm, E.A, van Zundert, W.J.H.P, … Jansen, M.P.H.M. (2016). SIAH2 protein expression in breast cancer is inversely related with ER status and outcome to tamoxifen therapy. American Journal of Cancer Research, 6(2), 270–284. doi:10.1158/1538-7445.SABCS15-P5-08-51