A240: Exploring the role of BCL11A in the EMT program and metastasis

Dorothy Yang1,Fazal Hadi1,Walid Khaled1

1Department of Pharmacology, University of Cambridge, Cambridge, UK

Presenting date: Monday 2 November
Presenting time: 13.10-14.00

Background

Breast cancer is a disease of molecular and cellular heterogeneity. Basal-like breast cancers (BLBC) tend to carry particularly unfavourable prognoses due to the lack of effective targeted therapies. They are associated with activation of the epithelial-to-mesenchymal (EMT) program which relates to the stem-cell-like and metastatic characteristics of these tumours. The transcription factor BCL11A has been found to be overexpressed in a large majority of BLBC cases, suggesting its role as an important BLBC oncogene. Furthermore, BCL11A overexpression has been found to increase invasive and metastatic potential in basal-like breast cancer cell lines, suggesting an involvement in the EMT program.

Method

Here, I used quantitative PCR to compare the expression of selected EMT transcription factors, and epithelial and mesenchymal markers, in wild-type and BCL11A knockdown cell lines.

Results

A striking increase in mRNA levels of c-FOS, a transcriptional activator for key epithelial proteins, was observed in BCL11A knockdown cells compared to wild-type. However, this dramatic increase was not replicated as convincingly in Western blots comparing c-FOS and phospho-c-FOS protein levels between wild-type and knockdown cells. Furthermore, mRNA levels of FRA-1, a gatekeeper of activation of the EMT program, were increased in knockdown cells, while mRNA levels of Crumb3 and Claudin-3, epithelial markers, were decreased in knockdown cells, results seemingly inconsistent with BCL11A's hypothesised role in promoting the mesenchymal phenotype.

Conclusion

Thus, while there is strong evidence for a pro-metastatic role for BCL11A, possibly associated with a depletion of c-FOS activity, the specific pathways by which these effects are achieved have yet to be fully elucidated. Further elucidation will inform the development of approaches to target the EMT program therapeutically, and reveal the viability of the BCL11A interaction network as targets for BLBC therapy.