Hope for Targeted Therapies in Aggressive Breast Cancer

Liam Davenport

January 14, 2015

The development and progression of triple-negative breast cancer might be driven by the overexpression of a transcription-factor gene, which means there is hope for targeted therapy in this aggressive form of the disease.

British researchers have found that BCL11A is highly expressed in triple-negative tumors, specifically the basal-like subtype. The overexpression promotes tumor development and deletion reduces tumor formation. Furthermore, inactivation of the gene caused regression in established tumors.

"Triple-negative breast cancer has the poorest survival rates among subtypes of breast cancer, and at present there aren't really targeted therapies available, leaving chemotherapy as one of the main treatment options," said colead author Walid T. Khaled, PhD, from the Wellcome Trust Sanger Institute and the University of Cambridge in the United Kingdom.

"We wanted to focus on these genes because we knew they were very important in other systems, such as the metabolic system. They are important in determining cell fate, [in that] they are transcription factors," he told Medscape Medical News.

"These things don't really need to be heavily overexpressed to drive major change because they are the master regulators of transcription," he explained.

The study was published online January 9 in Nature Communications.

To identify potential oncogenes for triple-negative breast cancer, the team initially selected genes known to be involved in hematopoiesis and examined their expression in the major breast cancer molecular subtypes.

Analysis of a publicly available microarray dataset revealed that the BCL11A gene was differentially and highly expressed in basal-like breast cancer, a subtype of triple-negative breast cancer.

The researchers used two datasets — METABRIC (Nature. 2012;486:346-352) and The Cancer Genome Atlas Network (Nature. 2012;490:61-70) — which contain curated gene expression, copy number variation, and clinical data for almost 3000 breast cancer patients. They found that high BCL11A expression was significantly correlated with triple-negative breast cancer pathology and high histologic grade.

Immunohistochemical analysis of a subset of 368 tumors, 24 of which were basal-like breast cancers, from the METABRIC dataset validated the high expression of BCL11A in basal-like breast cancers. Furthermore, 38% of basal-like breast cancers from The Cancer Genome Atlas dataset had BCL11A copy number gains. Patients with either high expression or copy number gains had poorer survival rates than other patients.

Experiments in xenograft mouse models indicated that exogenous overexpression of BCL11A promoted tumor expression, whereas knockdown of the gene suppresses tumorigenic potential.

Moreover, BCL11A deletion in a mouse model substantially decreased tumor formation, even in p53-null mice, and BCL11A inactivation in established tumors caused tumor regression.

Finally, the researchers were able to demonstrate that, at the cellular level, the deletion of BCL11A led to a reduction in the number of mammary epithelial stem and progenitor cells. This, Dr Khaled explained, suggests that the overexpression of BCL11A in these cell types is one of the initiating steps in triple-negative breast cancer tumors.

It remains to be seen, however, whether these findings take us a step closer to individualizing care for patients with triple-negative breast cancer, Dr Khaled cautioned. "We obviously don't want to have false hope," he said.

"I would love to tell you that in the oncology clinic we should have a test for BCL11A and, based on the tests, we would decide what to do. Maybe that would be something that we will do eventually in the future," he noted, "but based on this single study, we can't say if that will be the case."

"We will need to do even larger patient studies where we stain even more samples," he explained. "For this study, we stained almost 400 samples out of 2000 for BCL11A protein expression. In that, you could clearly identify the subset of patients; based on that, maybe we should be able to give them treatment."

Targeted therapies could be on the horizon. Eventually, "we could have a very targeted therapeutics for triple-negative tumors," he said.

In fact, "we are doing a drug screen in collaboration with Cancer Research UK to try to find potential inhibitors of BCL11A, given the very unmet clinical need for targeted therapeutics for this type of breast cancer," he reported.

This work was supported by the Wellcome Trust and the Wellcome Trust Sanger Institute. Dr Khaled reports receiving support from the Biotechnology and Biological Sciences Research Council (BBSRC), King's College in Cambridge, and Cancer Research UK. Coauthor John Stingl, PhD, from Cancer Research UK and the University of Cambridge, reports receiving support from Hutchison Whampoa Ltd. Coauthor Christine Watson, PhD, from the University of Cambridge, reports receiving support from BBSRC, the Medical Research Council, and the Breast Cancer Campaign.

Nat Commun. Published online January 9, 2015. Abstract

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