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.2010 Jan 19;102(2):361-8.
doi: 10.1038/sj.bjc.6605478. Epub 2009 Dec 15.

PSMB7 is associated with anthracycline resistance and is a prognostic biomarker in breast cancer

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PSMB7 is associated with anthracycline resistance and is a prognostic biomarker in breast cancer

G Munkácsy et al. Br J Cancer..

Abstract

Background: To date individual markers have failed to correctly predict resistance against anticancer agents in breast cancer. We used gene expression patterns attributable to chemotherapy-resistant cells to detect potential new biomarkers related to anthracycline resistance. One of the genes, PSMB7, was selected for further functional studies and clinical validation.

Methods: We contrasted the expression profiles of four pairs of different human tumour cell lines and of their counterparts resistant to doxorubicin. Observed overexpression of PSMB7 in resistant cell lines was validated by immunohistochemistry. To examine its function in chemoresistance, we silenced the gene by RNA interference (RNAi) in doxorubicin-resistant MCF-7 breast cancer cells, then cell vitality was measured after doxorubicin treatment. Microarray gene expression from GEO raw microarray samples with available progression-free survival data was downloaded, and expression of PSMB7 was used for grouping samples.

Results: After doxorubicin treatment, 79.8+/-13.3% of resistant cells survived. Silencing of PSMB7 in resistant cells decreased survival to 31.8+/-6.4% (P>0.001). A similar effect was observed after paclitaxel treatment. In 1592 microarray samples, the patients with high PSMB7 expression had a significantly shorter survival than the patients with low expression (P<0.001).

Conclusion: Our findings suggest that high PSMB7 expression is an unfavourable prognostic marker in breast cancer.

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Figures

Figure 1
Figure 1
Overview of the statistical analysis.
Figure 2
Figure 2
Discriminating transcripts: (A) hierarchical clustering of all three groups (parental, treated parental, resistance cell line) against each other and (B) hierarchical clustering of parentalvs treated parental cell lines. Red arrows show appearance of three probe sets measuring proteasome subunits on resistance-associated gene list. Immunohistochemical localization ofPSMB7 expression in sensitive (C) and resistant cells (D). Reactions of cytoplasmic localization were obtained forPSMB7 (green arrows).
Figure 3
Figure 3
(A) Schematic view ofPSMB7 gene with its eight exons. Splitting positions of tested siRNA oligos are shown (↓); the most effective siRNA is marked by continuously bordered box. Binding location of designed PCR primers specific forPSMB7 is shown under the gene by a broken line (↓). Positions of probe sequences of probeset 200786_at on Affymetrix HG-U133A array are also shown (▴, match probes; ▵, junction probes, overlapping two neighbouring exons). (B) Details of designed siRNA oligos. One out of three siRNA oligos (degrading at 548 nucleotide (nt)) showed effective silencing compared with siRNA-untreated control.GAPDH was used as internal control for both untreated control and siRNA-treated samples. The effect ofsilencing was 87% for siRNA binding at position 548.
Figure 4
Figure 4
The effect of silencing ofPSMB7 on doxorubicin resistance in MCF-7 cells.
Figure 5
Figure 5
Kaplan–Meier of survival of the 1592 breast cancer patients grouped by the expression ofPSMB7 (200786_at probe set) above or below the median.
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