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Research Project
The functional role of long non-coding RNAs in epithelialmesenchymal transition (EMT) and malignant breast cancer
progression
Third-party funded project
Project title The functional role of long non-coding RNAs in epithelial-mesenchymal transition (EMT) and
malignant breast cancer progression
Principal Investigator(s) Christofori, Gerhard M.;
Organisation / Research unit Departement Biomedizin / Tumor Biology (Christofori)
Project start 01.08.2016
Probable end 30.07.2017
Status Active
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 noncoding 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.
Keywords Cancer, EMT, lncRNA, Metastasis
Financed by
Foundations and Associations
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