title: SIAH2 protein expression in breast cancer is inversely related with ER status and outcome to tamoxifen therapy.
abstract: 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.
authors.affiliation: Department of Medical Oncology and Cancer Genomics Netherlands, Erasmus MC Cancer Institute, Erasmus University Medical Center Rotterdam, The Netherlands.
authors.forename: Kimberly D
authors.initials: KD
authors.lastname: van der Willik
authors.affiliation: Department of Medical Oncology and Cancer Genomics Netherlands, Erasmus MC Cancer Institute, Erasmus University Medical Center Rotterdam, The Netherlands.
authors.forename: Mieke M
authors.initials: MM
authors.lastname: Timmermans
authors.affiliation: Department of Medical Oncology and Cancer Genomics Netherlands, Erasmus MC Cancer Institute, Erasmus University Medical CenterRotterdam, The Netherlands; Department of Pathology, Erasmus MC Cancer Institute, Erasmus University Medical CenterRotterdam, The Netherlands.
authors.forename: Carolien Hm
authors.initials: CH
authors.lastname: van Deurzen
authors.affiliation: Department of Medical Oncology and Cancer Genomics Netherlands, Erasmus MC Cancer Institute, Erasmus University Medical Center Rotterdam, The Netherlands.
authors.forename: Maxime P
authors.initials: MP
authors.lastname: Look
authors.affiliation: Department of Medical Oncology and Cancer Genomics Netherlands, Erasmus MC Cancer Institute, Erasmus University Medical Center Rotterdam, The Netherlands.
authors.forename: Esther A
authors.initials: EA
authors.lastname: Reijm
authors.affiliation: Department of Medical Oncology and Cancer Genomics Netherlands, Erasmus MC Cancer Institute, Erasmus University Medical Center Rotterdam, The Netherlands.
authors.forename: Wendy Jhp
authors.initials: WJ
authors.lastname: van Zundert
authors.affiliation: Department of Medical Oncology and Cancer Genomics Netherlands, Erasmus MC Cancer Institute, Erasmus University Medical Center Rotterdam, The Netherlands.
authors.forename: Renée
authors.initials: R
authors.lastname: Foekens
authors.affiliation: Department of Medical Oncology and Cancer Genomics Netherlands, Erasmus MC Cancer Institute, Erasmus University Medical Center Rotterdam, The Netherlands.
authors.forename: Anita Mac
authors.initials: AM
authors.lastname: Trapman-Jansen
authors.affiliation: Department of Pathology, Erasmus MC Cancer Institute, Erasmus University Medical CenterRotterdam, The Netherlands; Department of Pathology, Maasstad HospitalRotterdam, The Netherlands.
authors.forename: Michael A
authors.initials: MA
authors.lastname: den Bakker
authors.affiliation: Laboratory for Pathology Dordrecht, The Netherlands.
authors.forename: Pieter J
authors.initials: PJ
authors.lastname: Westenend
authors.affiliation: Department of Medical Oncology and Cancer Genomics Netherlands, Erasmus MC Cancer Institute, Erasmus University Medical Center Rotterdam, The Netherlands.
authors.forename: John Wm
authors.initials: JW
authors.lastname: Martens
authors.affiliation: Department of Medical Oncology and Cancer Genomics Netherlands, Erasmus MC Cancer Institute, Erasmus University Medical Center Rotterdam, The Netherlands.
authors.forename: Els Mjj
authors.initials: EM
authors.lastname: Berns
authors.affiliation: Department of Medical Oncology and Cancer Genomics Netherlands, Erasmus MC Cancer Institute, Erasmus University Medical Center Rotterdam, The Netherlands.
authors.forename: Maurice Phm
authors.initials: MP
authors.lastname: Jansen
keywords: Seven-in-absentia-homolog 2; breast cancer; endocrine therapy resistance; immunohistochemistry; tissue microarray