PD10-07: microRNA Profiles of Breast Tumors Identifies the miR 17–92 Cluster as a Group of Potentially Essential Oncomirs in Triple-Negative Breast Cancer.
Authors: Son BH , Birkbak NJ , Tian R , Iglehart D , Wang ZC , Richardson AL 
Published: June 2012

Introduction: MicroRNAs (miRNAs) are a class of short non-coding RNAs of about 20–24 nucleotides that act post-transcriptionally to modulate gene expression by sequence-specific base-pairing with target mRNAs. While the function of human miRNA remains largely unknown, certain miRNAs have previously been implicated in cancer development and progression. In this study, we investigate the expression of 734 miRNAs across a cohort of 7 normal breast samples and 104 breast cancer tumors including 70 ER−/PR−/HER2−(triple negative, TN), 15 ER+/PR+, and 19 HER2+.

Methods: We used the novel Nanostring technology to quantify the expression of 734 miRNAs. Unsupervised hierarchical clustering was performed using miRNAs that were detected as expressed in at least one sample. A two-sided Wilcoxon rank sum test was used to identify miRNAs with a significantly differential expression between two sets of samples.

Results: In agreement with previously published results, we found that tumor samples clustered into the luminal and TN subtypes using unsupervised hierarchical clustering on the expressed miRNAs. Interestingly, microRNA expression was similar between HER2 amplified ER+ and HER2 amplified ER−, suggesting a common luminal origin. When we specifically compared luminal (ER+ or HER2+) to TNBC, we found that 50 miRNAs showed significant differential expression. In particular, the miR-17-92 cluster(1) was expressed at significantly higher levels in TN tumors. Within the luminal tumors the miR-17-92 cluster was strongly correlated with proliferation and grade; although miR17-92 was expressed at high level, there was no correlation with proliferation in the TN tumors. miR17-92, which inhibits translation of E2F1(1), is in a regulatory network with myc and E2F to control the balance between proliferation and apoptosis(2). The absence of correlation between miR17-92 and proliferation in the TN tumors suggests disruption of this regulatory network. Indeed, we found a positive correlation between expression of miR17-92 and p16 and inverse correlation with RB across the tumor set. The high p16/low RB expression in TN tumors is consistent with disruption of the RB pathway (3) and suggest these TN tumors may depend on miR17-92 to down-modulate expression of E2F1 which would otherwise induce apoptosis.

Conclusions: Our results show that miRNA expression in breast cancer tumors differs depending on subtype. We also find evidence to suggest subtype-specific miRNA regulation of proliferation and a particular dependency of TN tumors on the miR17-92 cluster for survival.

References:

1. Novotny et al. Translational repression of E2F1 mRNA in carcinoma in situ and normal testis correlates with expression of the miR-17-92 cluster. Cell Death Differ. 2007.

2. Aguda et al. MicroRNA regulation of a cancer network: Consequences of the feedback loops involving miR-17-92, E2F, and Myc. PNAS 2009.

3. Subhawong et al. Most basal-like breast carcinomas demonstrate the same Rb−/p16+ immunophenotype as the HPV-related poorly differentiated squamous cell carcinomas which they resemble morphologically. Am J Surg Pathol. 2009.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr PD10-07.