Scientists from the Wellcome Trust Sanger Institute in Cambridge have stumbled upon a gene involved in the development and growth of triple negative breast cancer, which could open up avenues for the design of new treatments. Dr Matthew Lam takes a closer look at the research to find out what impact this could have in the future for women with TNBC.

Thursday 15 January 2015      Research blog
BCL11A - the positive in triple negative

Last weekend there was some interesting research reported in the news about a significant advance in our understanding of triple negative breast cancer (TNBC).

We wrote about this aggressive form of the disease last week, explaining how identifying the features that make these patients stand out from the crowd is key to the discovery of effective targeted treatments.

Scientists from the Wellcome Trust Sanger Institute in Cambridge have now stumbled upon a gene involved in the development and growth of TNBC, which could open up avenues for the design of new treatments.

Dr Matthew Lam takes a closer look at the research to find out what impact this could have in the future for women with TNBC.

How common is TNBC?

TNBC makes up between 10-20% of all breast cancer cases and, as of yet, no effective targeted treatments exist for these people.

Targeted treatments have helped push the number of women surviving five years after a breast cancer diagnosis to around 93%, but the lack of treatment options for TNBC is starkly reflected in the fact that for these women, the figure is reduced to 77%.

The BCL11A gene

The BCL11A gene carries the instructions the cell uses to build a protein known to be involved in deciding the fate of stem cells. Scientists describe these cells as being “pluripotent”, which means that under different conditions they can become any cell type in the body.

BCL11A plays a role in coaxing stem cells into cells of the immune system.  Back in 2003, scientists showed that messing around with how this gene works during embryonic development could cause mice to develop leukaemia, a form of cancer associated with the immune system. But what about other types of cancer?

BCL11A and TNBC

The researchers in Cambridge took a list of genes and, using genetic data collected from breast cancer patients, sought to identify which genes were broken or dysfunctional in women with TNBC. They found that the BCL11A gene was “highly expressed” in TNBC – meaning that the gene was causing the cell to pump out more of the BCL11A protein than usual.

To understand what the impact of highly expressing BCL11A is on breast cells, they took to manipulating the genetics of cells in the lab. The team forced breast cells to switch on the BCL11A gene more aggressively than normal, which made the cells more likely to show characteristics associated with tumour cells.

It’s a knockout

To fully study the effects of the BCL11A gene on breast cancer, the team needed to breed mice that didn’t have BCL11A. Creating a “knockout” mouse would normally do this – a technique involving breeding of mice with the gene artificially removed, or “knocked out”. However, the BCL11A gene plays an important role in embryonic development, so if the gene is missing, mice don’t develop properly and embryos are terminated.

The researchers overcame this problem by using a highly sophisticated technique called a “conditional gene knockout”. This allows genes to be “knocked out” in a specific tissue or organ (such as the mammary gland) rather than in every cell in the body. This targeted engineering allowed the team to do just that, and they developed a mouse with the BCL11A gene specifically “knocked out” of the mammary gland.

Mice carrying BCL11A were much more likely to develop tumours and, interestingly, when BCL11A was “knocked out” after a tumour had formed, the tumour stopped growing and reduced in size.

This is quite remarkable as it demonstrates that not only does BCL11A cause tumours to form but that targeting the gene can also cause them to regress.

What next for TNBC?

This study has revealed a new breast cancer gene, which is specifically relevant to women with TNBC. It shows that this gene could be used to determine which patients with TNBC would benefit from drugs targeted towards BCL11A.  As there are no targeted treatments for TNBC, this really is an exciting result that one day may lead to better treatments for women with this type of breast cancer.

Although the researchers have begun to pull apart how this gene is related to breast cancer there is still work to do. It is still unknown if the results seen in the “knockout” mice can also be expected in humans but the fact that this gene is highly expressed in around 80% of TNBC patients shows promise for future drugs to be developed against this gene.

Dr Matthew Lam is Breakthrough Breast Cancer's Senior Research Officer