Downregulation of SIAH2, an ubiquitin E3 ligase, is associated with resistance to endocrine therapy in breast cancer.

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.

• 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
• Journal: Breast cancer research and treatment (Breast Cancer Res Treat) Vol. 116 Issue 2 Pg. 263-71 (Jul 2009) ISSN: 1573-7217 [Electronic] Netherlands
• PMID: 18629630 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents, Hormonal
• Biomarkers, Tumor
• Nuclear Proteins
• RNA, Messenger
• Selective Estrogen Receptor Modulators
• Estradiol
• Epidermal Growth Factor
• Ubiquitin-Protein Ligases
• seven in absentia proteins
• ErbB Receptors

Topics

• Adult
• Aged
• Antineoplastic Agents, Hormonal (therapeutic use)
• Biomarkers, Tumor (genetics)
• Blotting, Western
• Breast Neoplasms (drug therapy, genetics, pathology)
• Disease-Free Survival
• Drug Resistance, Neoplasm (genetics)
• Epidermal Growth Factor (metabolism)
• ErbB Receptors (genetics, metabolism)
• Estradiol (metabolism)
• Female
• Humans
• Kaplan-Meier Estimate
• Middle Aged
• Nuclear Proteins (genetics, metabolism)
• Oligonucleotide Array Sequence Analysis
• Prognosis
• RNA, Messenger (analysis)
• Reverse Transcriptase Polymerase Chain Reaction
• Selective Estrogen Receptor Modulators (therapeutic use)
• Treatment Outcome
• Ubiquitin-Protein Ligases (genetics, metabolism)