Downregulation of SIAH2, an ubiquitin E3 ligase, is associated with resistance to endocrine therapy in breast cancer |
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Authors: | Maurice P H M Jansen Kirsten Ruigrok-Ritstier Lambert C J Dorssers Iris L van Staveren Maxime P Look Marion E Meijer-van Gelder Anieta M Sieuwerts Jozien Helleman Stefan Sleijfer Jan G M Klijn John A Foekens Els M J J Berns |
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Institution: | (1) Department of Medical Oncology, Erasmus MC, Josephine Nefkens Institute, Room Be401, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands;(2) Top Institute (TI) Pharma, Rotterdam, The Netherlands;(3) The Netherlands Genomics Center, Rotterdam, The Netherlands;(4) Department of Pathology, Erasmus MC, Josphine Nefkens Institute, Rotterdam, The Netherlands |
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Abstract: | Purpose In our microarray analysis we observed that Seven-in-Absentia Homolog 2 (SIAH2) levels were low in estrogen receptor (ER)
positive breast tumors of patients resistant to first-line tamoxifen therapy. The aim of this study was to evaluate SIAH2
for its (a) predictive/prognostic value, and (b) functional role in endocrine therapy resistance. Patients and methods SIAH2 expression was measured with quantitative Real-Time-PCR (qRT-PCR) in 1205 primary breast tumor specimens and related
to disease outcome. The functional role of SIAH2 was determined in human breast cancer cell lines ZR-75-1, ZR/HERc, and MCF7.
Cell lines were treated with estrogen (E2), anti-estrogen ICI164.384 or epidermal growth factor (EGF). Moreover, MCF7 was
treated with ICI164.384 after silencing SIAH2 expression. Results SIAH2 was not prognostic in 603 lymph node negative patients who had not received adjuvant systemic therapy. In multivariate
analysis of ER-positive tumors of 235 patients with recurrent disease, SIAH2 as continuous variable, significantly predicted
first-line tamoxifen treatment failure (OR = 1.48; P = 0.05) and progression-free survival (PFS) (HR = 0.79; P = 0.007). Furthermore, in primary breast cancer patients treated with adjuvant tamoxifen, SIAH2 predicted metastasis-free
survival (MFS) (HR = 0.73; P = 0.005). In vitro experiments showed that SIAH2 silencing in MCF7 cells resulted in resistance to ICI164.384-treatment when
compared with mock silenced cells (P = 0.008). Interestingly, in ZR cells transfected with EGFR (ZR/HERc), SIAH2 expression was induced by E2 but downregulated
by EGF. Conclusion In primary breast tumor specimens as well as in vitro low SIAH2 levels associated with resistance to endocrine therapy. Moreover,
SIAH2 expression showed an opposite regulation by E2 and EGF. |
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Keywords: | SIAH2 Ubiquitin E3 ligase Endocrine therapy resistance siRNA Breast tumors |
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