New research published in the Journal Cell has identified the gene (ZEB1) that is responsible for converting non aggressive basal type cancer into highly malignant, tumor forming cancer stem cells (CSCs). Basal type carcinoma is a highly aggressive form of breast cancer. Luminal breast cancer cells, which are associated with a much better clinical prognosis, carry this gene in a state in which it seems to be permanently shut down.
According to a 2011 epidemiological study, the 5-year survival rate for patients with basal breast cancer is 76%, compared with a roughly 90% 5-year survival rate among patients with other forms of breast cancer.
“We may have found a root source, maybe the root source, of what ultimately determines the destiny of breast cancer cells — their future benign or aggressive clinical behavior,” says Whitehead Founding Member Robert Weinberg, who is also a professor of biology at MIT and Director of the MIT/Ludwig Center for Molecular Oncology.
ZEB1 is involved in controlling the expression of other genes with its role in the epithelial-to-mesenchymal transition (EMT), during which epithelial cells acquire the traits of mesenchymal cells. Unlike the tightly-packed epithelial cells that stick to one another, mesenchymal cells are loose and free to move around a tissue. Previous work in the Weinberg lab showed that adult cancer cells passing through an EMT are able to self-renew and to seed new tumors with high efficiency, hallmark traits of CSCs.
Breast cancers are categorized into at least five different subgroups based on their molecular profiles. More broadly these groups can be subdivided into the less aggressive ‘luminal’ subgroup or more aggressive ‘basal’ subgroup. The aggressive basal-type breast cancers often metastasize, seeding new tumors in distant parts of the body. Patients with basal breast cancer generally have a poorer prognosis than those with the less aggressive luminal-type breast cancer.
The scientists determined that the difference in ZEB1’s effects is due to the way the gene is marked in the two types of cancers. In luminal breast cancer cells, the ZEB1 gene is occupied with modifications that shut it’s activity down. In basal breast cancer cells, ZEB1’s state is more tenuous, with repressing and activating markers coexisting on the gene. When these cells are exposed to certain signals, the repressive marks are removed and ZEB1 is expressed, thereby converting the basal non-CSCs into CSCs.
Christine L. Chaffer, Nemanja D. Marjanovic, Tony Lee, George Bell, Celina G. Kleer, Ferenc Reinhardt, Ana C. D’Alessio, Richard A. Young, Robert A. Weinberg. Poised chromatin at the ZEB1 promoter enables breast cancer cell plasticity and enhances tumorigenicity. Cell, 2013 DOI: 10.1016/j.cell.2013.06.005