Discovery of the on-off switch for triple negative breast cancer

Research by the Garvan Institute in Sydney Australia by Dr. Alex Swarbrick and Dr. Simon Junankar, et al has found the genetic on-off switch for triple negative breast cancer. Their research, published in Nature Communications, DOI: 10.103/ncomms7548, says they have been able to "switch" triple negative breast cancer (TNBC) to a treatable version by using ID4 to suppress the mammary stem cells. TNBC accounts for approximately 15% of all breast cancer and afflicts both men and women.

TNBCs lack the three receptors (estrogen, progesterone, and HER2) that make them responsive to targeted medication like Tamoxifen and aromatase inhibitors.

They found that TNBCs are diverse. Some types have prospects as good as other forms of BC whereas others are difficult to impossible to successfully treat. TNBC can be categorized as two distinct diseases which the researchers believe have different origins. One form of TNBC is enriched in stem cells. The research is not finalized but Swarbrick says if they are successful in switching TNBC to estrogen-positive BC the disease could be successfully treated.

ID4 gene is produced at high levels in roughly half of all triple negative breast cancers says Dr. Swarbrick. These cancers have a poor prognosis. Those with no stem cell involvement have a higher treatment success. High levels of ID4 are produced by roughly half of all TNBCs.

"Stem cells share similar traits to cancer cells in that they both have a long live, are resistant to treatment and have an unlimited capacity to divide." Judy Motti, TechTimes, March 29, 2015.

Their research based on blocking ID4 demonstrated that the tumor cells stopped dividing. When the ID4 gene is suppressed, estrogen receptors are switched on in the tumors, possibly converting them to the very treatable estrogen receptor-positive BC types which can be treated with Tamoxifen.

According to an article by Michael Slezak in New Scientist, April 4, 2015, other genes also play a role in whether a tumor is susceptible to therapy, so this might not be the whole story. Swarbrick’s team is now looking to see if the switched tumors respond to Tamoxifen.

Latest information on a new gene that drives triple-negative breast cancer

Breast cancer cells
New information on a new gene that drives triple-negative breast cancer can be found on: Medical News Today: Image (left) is from the Jan 11, 2015 Medical News Today article.

Another article on the topic Novel breast cancer gene found - BCL11A by team from Cambridge University and Wellcome Trust Sanger Institute, UK. can be found on: (below).

Novel breast cancer gene found BCL11A is a triple-negative breast cancer gene with critical functions in stem and progenitor cells - Khaled, WT, Lee SC et al...

A new study identifies a gene that is especially active in aggressive subtypes of breast cancer. The research suggests that an overactive BCL11A gene drives triple-negative breast cancer development and progression.

The research, which was done in human cells and in mice, provides new routes to explore targeted treatments for this aggressive tumour type.

There are many types of breast cancers that respond differently to treatments and have different prognoses. Approximately, one in five patients is affected by triple-negative breast cancer; these cancers lack three receptor proteins that respond to hormone therapies used for other subtypes of breast cancer. In recent years it has become apparent that, the majority of triple-negative tumours are of the basal-like subtype.

Although new treatments are being explored, the prognosis for triple-negative cancer is poorer than for other types. To date, only a handful of genomic aberrations in genes have been associated with the development of triple-negative breast cancer.

The team looked at breast cancers from almost 3000 patients. Their search has a particular focus: they examined changes to genes that affect the behaviour of stem cells and developing tissues, because other work they have done suggests that such genes, when mutated, can often drive cancer development. Among these was BCL11A.

“Our understanding of genes that drive stem cell development led us to search for consequences when these genes go wrong,” says Dr 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.”

Higher activity of the BCL11A gene was found in approximately eight out of ten patients with basal-like breast cancer and was associated with a more advanced grade of tumour. In cases where additional copies of the BCL11A gene were created in the cancer, the prospects for survival of the patient were diminished.

“Our gene studies in human cells clearly marked BCL11A as a novel driver for triple-negative breast cancers,” says Dr Walid T. Khaled, joint first and senior author on the study from the Wellcome Trust Sanger Institute and University of Cambridge. “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.”

When BCL11A was inactivated in an experimental system in mice, no mice developed tumours in the mammary gland, whereas all untreated animals developed tumours.

The team also showed that BCL11A is required for normal development of breast stem cells and progenitors, which are thought to be the cells that, when mutated, give rise to basal-like breast cancer.

“This exciting result identifies a novel breast cancer gene in some of the more difficult-to-treat cases,” says Professor Carlos Caldas, Professor of Cancer Medicine and Director of the Cambridge Breast Cancer Research Unit at the University of Cambridge, and Head of Breast Cancer Functional Genomics at Cancer Research UK Cambridge Institute. “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.”

The team propose that BCL11A is a strong candidate for development of a possible targeted treatment.

Publication Details
Khaled, WT, Lee SC et al. (2015) BCL11A is a triple-negative breast cancer gene with critical functions in stem and progenitor cells. Nature Communications doi: 10.1038/ncomms6987
Read a short article about the findings on Medical News Today:
A more detailed article can be found at

How breast cancer cells break free to spread in the body

A recent ScienceDaily article about how breast cancer cells spread into the body is based on research at the Georgia Institute of Technology, ScienceDaily 12,17,14. It states the study shows more than 90 percent of cancer-related deaths are caused by the spread of cancer cells from their primary tumor site to other areas of the body. This new study has identified how one important gene helps cancer cells break free from the primary tumor. Read the full article at:

MCF-7 Human breast cancer cells - credit: MgGrail, et al., FASEB 2014















Pictured above are MCF-7 human breast cancer cells, stably transformed with SNAIL (right) or an empty vector control (left). Cells expressing SNAIL show an increased mesenchymal phenotype and malignant characteristics. The control cells display a cobblestone morphology, whereas cells overexpressing SNAIL are more elongated.