Breast cancer is the leading cause of cancer-related mortality in women globally. While patients with localized primary breast cancer often have a good prognosis and can be treated effectively, 90% of all cancer-related deaths are due to the systemic dissemination of cancer cells and metastatic outgrowth [1]. Thus, understanding the molecular pathways underlying malignant tumor progression and metastasis formation is critical for the development of innovative and efficacious cancer therapies.

During the transition to metastasis formation, tumor cells acquire an invasive phenotype accompanied by dramatic changes in cellular morphology and the gain of invasive capabilities. These changes are hallmarks of an Epithelial-Mesenchymal-Transition (EMT), a process involving a dramatic reprogramming of cancer cells [2]. However, during an EMT cells also acquire profound survival capabilities and can overcome cell death and immune surveillance and even resist chemotherapy. Moreover, cancer cells undergoing EMT exhibit hallmarks of cancer stem cells; they are able to maintain cancer cell growth and initiate new tumors [3].

Previously considered as transcriptional noise, recent studies have elucidated the importance of long non-coding RNAs (lncRNAs), transcripts greater than 200 nucleotides without any evident protein coding function. LncRNAs play important regulatory roles in diverse physiological processes, such as proliferation, cell cycle, apoptosis and differentiation [4]. Moreover, the expression of many lncRNAs has been found to be dysregulated in cancer suggesting a critical role in tumorigenesis [5, 6]. We speculate that lncRNAs might also play an important role in EMT and in malignant breast cancer progression and metastasis. Hence, the identification and functional characterization of novel lncRNAs regulating these processes will offer new opportunities to therapeutically restrain breast cancer metastasis-related mortality and morbidity.

Recently, we have used whole transcriptome RNA-Sequencing to identify ~100 novel lncRNAs that are regulated in their expression during the multistage process of an EMT, which we refer to as EMT-associated transcripts (ETs). Interestingly, many of these lncRNAs are expressed from genomic loci encoding for EMT and metastasis-associated genes. Of particular interest is the novel lncRNA ET-20 that overlaps with the Tenascin C (TNC) gene, an extra-cellular matrix protein shown to be important for EMT and metastatic outgrowth of breast cancer cells [7]. ET-20 and TNC are co-expressed in several models of EMT and breast cancer, and knockdown of ET-20 prevents cell migration and invasion and also the expression of TNC and other markers of EMT. On the basis of our current results, we speculate that the expression of ET-20 and TNC is coordinately controlled by the transcription factor Sox4, a master regulator of an EMT and metastasis [8]. A number of other novel ET lncRNAs are also co-expressed with well-known metastasis genes. Here, we propose to unravel the molecular mechanism by which ETs regulate EMT and breast cancer invasion and metastasis. In the long run, we envision to exploit the functional role of differentially regulated ETs for the design of novel cancer therapies.