Changes to intermediate filament protein drive aggressive breast cancer growth

Changes to the intermediate filament (IF) protein, vimentin, were found to promote tumor growth by increasing cancer stemness in an estrogen independent manner. Targeting vimentin and/or the long noncoding RNA (lncRNA) 'XIST' could be an effective therapeutic strategy for treating aggressive breast cancer. 

Vimentin is a type III intermediate filament (IF) protein normally expressed in cells that develop into connective tissue, blood vessels, and lymphatic tissue (mesenchymal cells). Despite being widely studied, its role in tumor growth and progression remains unexplored. 

A team of researchers at Queen Mary University of London have discovered how a small change in the vimentin protein can make breast cancer more aggressive. By modifying a specific amino acid cysteine to serine residue at position 328 in vimentin, they discovered that this mutation disrupted the protein's interaction with the cell's structural network. Remarkably, the mutated vimentin induced aggressive cancer-like behavior in breast cancer cells, including faster cell growth, migration, and invasion accompanied by reduced cell adhesion. RNA-sequencing further revealed that the presence of mutant vimentin was associated with upregulation of a non-coding RNA called XIST, suggesting a potential link between this mutation and gene expression changes that drive cancer progression. 

Researchers also found that mutant vimentin made breast cancer cells grow without depending on the hormone oestrogen when injected into immuno-compromised mice. The tumors in these mice showed high expression of cancer stem cell markers CD56 and CD20, suggesting a role for mutant vimentin in driving cancer stem cell-like behaviour that is often associated with tumor progression, therapeutic resistance and recurrence. 

Senior author Ahmad Waseem, Professor of Molecular and Cellular Oral Biology at the Institute of Dentistry, Queen Mary University of London, said: "Our study has discovered a molecular interaction that, when disrupted, causes breast cancer cells to behave like cancer stem cells. Additionally, we identified a potential biomarker that could help detect these stem-like cells in breast cancer tissues. This discovery represents an important step towards understanding how breast cancer develops and spreads, with potential implications for early diagnosis, prognosis, and targeted treatment strategies." The lead author, Dr Saima Usman (HEC Fellow), did her PhD with Professor Waseem on this project. 

The study will open new avenues for our understanding of cancer stem cell behavior. For several years, Professor Waseem and I have been interested in studying the cancer-related roles of vimentin, which is induced in almost all later-stage tumors that have spread to other sites in the body and can be difficult to treat. We used MCF-7, a model breast epithelial cell line, partly because it is devoid of vimentin which therefore makes it easier to define functions related to specific vimentin mutations. Our observation that the cells became more aggressive, and that stem cell markers were induced, may unlock the door to new therapeutic approaches for breast and other cancers." 

Andrew Yeudall, Co-Author, Professor of Oral Biology, Dental College of Georgia at Augusta University