Abstract
The long-non-coding HOX transcript antisense intergenic RNA (HOTAIR) was identified as significantly upregulated in breast ductal carcinoma in situ (DCIS). The aim of this study was to characterize the phenotypic effects and signaling pathways modulated by HOTAIR in early-stage breast cancer progression. We determined that HOTAIR induces premalignant phenotypic changes by increasing cell proliferation, migration, invasion and in vivo growth in normal and DCIS breast cell lines. Transcriptomic studies (RNA-seq) identified the main signaling pathways modulated by HOTAIR which include bioprocesses related to epithelial to mesenchymal transition, cell migration, extracellular matrix remodeling and activation of several signaling pathways (HIF1A, AP1 and FGFR). Similar pathways were identified as activated in primary invasive breast carcinomas with HOTAIR over-expression. We conclude that HOTAIR over-expression behaves as a positive regulator of cell growth and migration both in normal and DCIS breast cells involved with early-stage breast cancer progression.
Highlights
Ductal carcinoma in situ (DCIS) is a premalignant lesion and non-obligate precursor to most invasive breast carcinomas (IBC)
We performed a comprehensive molecular profiling of ‘pure’ high-grade ductal carcinoma in situ (DCIS) lesions, providing the first catalogue of genomic, transcriptomic, methylation and gene pathway changes occurring at this pre-invasive breast cancer stage [2]
Among the most significantly upregulated long-noncoding RNAs (lncRNAs) we found HOX transcript antisense intergenic RNA (HOTAIR) (fold change (FC) = 32.7; false discovery rate (FDR) < 0.0001) when DCIS were compared with normal breast tissue (Figure 1A)
Summary
Ductal carcinoma in situ (DCIS) is a premalignant lesion and non-obligate precursor to most invasive breast carcinomas (IBC). The reasons on why only some DCIS lesions progress to the invasive stage remain unclear. We performed the first comprehensive molecular profiling of pure high-grade (HG) DCIS lesions, identifying the main genomic, transcriptomic, methylation and gene pathway changes occurring at this pre-invasive breast cancer stage [2]. RNA-seq profiling allowed us to identify HG-DCIS lesions with the most aggressive phenotypes, based on tumor intrinsic subtypes, proliferative, immune scores and in the activity of specific signaling pathways. Among the transcriptomic signatures of the most aggressive DCIS lesions, we identified the deregulated expression of almost 200 long-noncoding RNAs (lncRNAs), many of which might be associated with breast cancer progression.
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