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. 2012;7(5):e36170.
doi: 10.1371/journal.pone.0036170. Epub 2012 May 18.

Global microRNA expression profiling of high-risk ER+ breast cancers from patients receiving adjuvant tamoxifen mono-therapy: a DBCG study

Maria B Lyng  1 , Anne-Vibeke Lænkholm, Rolf Søkilde, Karina H Gravgaard, Thomas Litman, Henrik J Ditzel
Affiliations

Global microRNA expression profiling of high-risk ER+ breast cancers from patients receiving adjuvant tamoxifen mono-therapy: a DBCG study

Maria B Lyng et al. PLoS One. 2012.

Abstract

Purpose: Despite the benefits of estrogen receptor (ER)-targeted endocrine therapies in breast cancer, many tumors develop resistance. MicroRNAs (miRNAs) have been suggested as promising biomarkers and we here evaluated whether a miRNA profile could be identified, sub-grouping ER+ breast cancer patients treated with adjuvant Tamoxifen with regards to probability of recurrence.

Experimental design: Global miRNA analysis was performed on 152 ER+ primary tumors from high-risk breast cancer patients with an initial discovery set of 52 patients, followed by two independent test sets (N = 60 and N = 40). All patients had received adjuvant Tamoxifen as mono-therapy (median clinical follow-up: 4.6 years) and half had developed distant recurrence (median time-to-recurrence: 3.5 years). MiRNA expression was examined by unsupervised hierarchical clustering and supervised analysis, including clinical parameters as co-variables.

Results: The discovery set identified 10 highly significant miRNAs that discriminated between the patient samples according to outcome. However, the subsequent two independent test sets did not confirm the predictive potential of these miRNAs. A significant correlation was identified between miR-7 and the tumor grade. Investigation of the microRNAs with the most variable expression between patients in different runs yielded a list of 31 microRNAs, eight of which are associated with stem cell characteristics.

Conclusions: Based on the large sample size, our data strongly suggests that there is no single miRNA profile predictive of outcome following adjuvant Tamoxifen treatment in a broad cohort of ER+ breast cancer patients. We identified a sub-group of Tamoxifen-treated breast cancer patients with miRNA-expressing tumors associated with cancer stem cell characteristics.

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Conflict of interest statement

Competing Interests: The authors have read the journal’s policy and have the following conflicts: TL and RS were employed at Exiqon A/S during the study. They declare that they have no conflict of interest beyond that. The remaining authors declare that they have no conflict of interest. This does not alter the authors' adherence to all the PLoS ONE policies on sharing data and materials.

Figures

Figure 1
Figure 1. Heat-map of significantly differentially expressed miRNAs associated with outcome after adjuvant Tamoxifen treatment.
Data is based on the discovery set (p<6.6e-4, FDR 2.5% and variance >0.1). The green symbols above the heat-map indicate samples from patients with no recurrence, whereas the red symbols indicate samples from patients with recurrence. The heat-map is a standardized intensity plot with the intensities ranging from −2 (green) to +2 (red).
Figure 2
Figure 2. Kaplan-Meier plots of the 10 miRNAs identified in the discovery set.
The bold line represents the patients with a good prognosis, whereas the dotted line represents the poor-prognosis patients. A) Probability of recurrence. B) Probability of overall survival.
Figure 3
Figure 3. Association of miR-7 with tumor grade.
Grade 1 vs. 3 and Grade 2 vs. 3: p = 0.01, and Grade 1 vs. 2: p = 0.02). N = 52 patients (Discovery set).
See this image and copyright information in PMC

References

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