Defining the role of MYBL2 in breast cancer progression
Institution: Institute of Cancer and Genomic Science, University of Birmingham
Corresponding Researcher: Paloma Garcia
Data Link(s): NA
Keyword(s): MYBL2, metastasis, DNA-repair, EMT, stemness
Summary
The transcription factor MYBL2 (B-Myb) is upregulated in breast cancer and its associated with poor prognosis. MYBL2 overexpression promotes cell cycle progression, cell survival and cell fate changes (epithelial to mesenchymal transition, EMT), leading to increase cell proliferation, drug resistance, tissue invasion and metastasis. Whilst these processes are attributed to breast cancer stem cells (BCSC), the role of MYBL2 in BCSC remains unknown. Our preliminary work has shown that MYBL2-knockdown in BCSC reduces selfrenewal capacity and decreases the expression of important stem-cell and EMT-related genes. Hence, targeting MYBL2 could be a way of eradicating the cancer-initiating population. Aims Our hypothesis is that MYBL2 is an important regulator of BCSC function. Our main questions are: 1. Is MYBL2 regulating BCSC function in vivo? 2. What is the mechanism/s by which MYBL2 overexpression in BCSC promotes increase survival, drug resistance and cell fate changes? 3. Could we block cancer progression by modulating MYBL2 expression in BCSC together with key genes implicated in maintenance of genome integrity or EMT pathways? Techniques and Methodology MYBL2 expression will be depleted by infecting BCSC with doxycycline-inducible shRNA lentivirus, or overexpressed through infection with MYBL2 cDNA. Cell lines utilised will be: MCF-10A (mammary epithelial non-tumorogenic), MCF7 (ER+) and MDA-MB-231 (triple negative). Mechanistic and functional studies will include DNA-repair kinetic, changes in EMT, limited dilution to assess in vivo stem cell self-renewal, and shMYBL2/protein inhibitor combinations to block stem cell function. Clinical significance will be tested through the transplantation of patient derived xenografts transduced with doxycycline-inducible MYBL2 shRNA into immunocompromised mice, followed by drug treatment. Impact Functional validation of MYBL2 within BCSC, and the identification of drug combinations, could lead to the development of novel therapeutic strategies that specifically target this population, helping to prevent disease progression and significantly impacting on the lives of cancer patients.
