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BCL11A: a novel overactive triple-negative breast cancer gene
Exciting results from a new study suggest that an overactive gene called BCL11A drives the development and progression of the aggressive triple-negative breast cancer. The study, carried out in both human cells and in mice, is published in the journal Nature Communications.

Triple-negative breast cancer has a particularly poor prognosis, being associated with high incidence of recurrence and metastasis to sites including the brain and lung. Treatment is complicated by its lack of oestrogen receptor, progesterone receptor and the HER2 protein, all of which are targets for therapy in other forms of breast cancer, and very few genomic aberrations have been identified for triple-negative breast cancer. This lack of effective therapies for triple-negative breast cancer makes identification of underlying mechanisms and tailored therapies all the more important. Approximately 20% of patients are affected by triple-negative breast cancer; the majority of triple-negative tumours are of the basal-like subtype.

In the current study, breast cancers from nearly 3000 patients were examined in order to identify genetic changes associated with behaviour of stem cells and developing tissues. Previous work by the same research team had suggested that mutations to such genes often drives cancer development. One of these genes was BCL11A. Senior author Dr Pentao Liu of the Wellcome Trust Sanger Institute explains further: "Our understanding of genes that drive stem cell development led us to search for consequences when these genes go wrong. BCL11A activity stood out because it is so active in triple-negative cancers. It had all the hallmarks of a novel breast cancer gene."

The results indicated that increased BCL11A activity occurred in approximately 8 out of every 10 patients with basal-like breast cancer and was associated with a more advanced grade of tumour. If the copy number of the BCL11A gene was increased, survival prospects for the patient were reduced.  In a mouse cancer model, inactivation of BCL11A resulted in no tumour development in the mammary glands, while all mice in which the gene was not inactivated developed mammary tumours.
Manipulation of BCL11A in human and mouse cells impacted on their cancer-like properties. Joint first author Dr Walid Khaled of the Wellcome Trust Sanger Institute and University of Cambridge says: "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. 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 behaviour; by reducing it, we reduce cancer-like behaviour." The research team also established that BCL11A is needed for normal development of breast stem cells and their progenitor. It is thought that these are the cells which give rise to basal-like breast cancer upon mutation.

The research team have proposed that their results indicate BCL11A as a strong candidate for development of a possible targeted treatment of triple-negative breast cancer.

Reference: Khaled, WT, Lee SC et al. (2015) BLC11A is a triple-negative breast cancer gene with critical functions in stem and progenitor cells. Nature Communications, published online in advance of print publication; doi: 10.1038/ncomms6987
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