Study results released recently by the Wellcome Trust Sanger Institute (UK) have indicated that a specific gene, termed BCL11A, is especially active in aggressive breast cancer subtypes, and may drive triple-negative breast cancer development and progression. The findings could provide new routes for the exploration of targeted treatments for this breast cancer type.
Approximately one in five breast cancer patients is affected by triple-negative breast cancer, predominantly of the basal-like subtype. Notably, the cancer lacks three key receptor proteins that respond to conventional breast cancer hormone therapies, meaning that despite efforts to find new treatments, prognosis for triple-negative breast cancer patients is poorer than for other breast cancer types.
The team of researchers from the Wellcome Trust Sanger Institute examined breast cancers from approximately 3000 patients. Their work focused on identifying alterations to the genes responsible for controlling the behavior of stem cells and developing tissues, as these had been linked to cancer development in previous investigations.
“Our understanding of genes that drive stem cell development led us to search for consequences when these genes go wrong,” explained Pentao Liu, senior author on the study, from the Wellcome Trust Sanger Institute. “BCL11A activity stood out because it is so active in triple-negative cancers. It had all the hallmarks of a novel breast cancer gene.”
In approximately eight out of ten patients with basal-like breast cancer, heightened activity of the BCL11A gene was identified. In situations where there were additional copies of the BCL11A gene in the cancer, survival was reduced.
“Our gene studies in human cells clearly marked BCL11A as a novel driver for triple-negative breast cancers. We also showed that adding an active human BCL11A gene to human or mouse breast cells in the lab drove them to behave as cancer cells,” reported Walid Khaled (Wellcome Trust Sanger Institute and University of Cambridge), joint first author on the study.
“As important, when we reduced the activity of BCL11A in three samples of human triple-negative breast cancer cells, they lost some characteristics of cancer cells and became less tumorigenic when tested in mice. So by increasing BCL11A activity we increase cancer-like behavior; by reducing it, we reduce cancer-like behavior.”
The inactivation of BCL11A in an experimental mouse system resulted in no mice developing mammary gland tumors. In contrast to this, all untreated animals developed tumors.
In addition to these findings, the researchers also successfully highlighted that BCL11A is needed to ensure normal development of breast stem cells and progenitors, which when mutated are thought to cause basal-like breast cancer.
“This exciting result identifies a novel breast cancer gene in some of the more difficult-to-treat cases,” commented Carlos Caldas (University of Cambridge). “It builds on our work to develop a comprehensive molecular understanding of breast cancer that will inform clinical decisions and treatment choices. Finding a novel gene that is active in cancer should also help in the search for new treatments.”
Prior to this study, only a very small number of genomic aberrations in genes had been linked to triple-negative breast cancer development. The team now believe that these findings place BCL11A as a strong candidate for the development of targeted treatments.