Singapore scientists uncover gene associated with an aggressive breast cancer

Singapore—Scientists at A*STAR's Genome Institute of Singapore (GIS), in collaboration with local clinicians and colleagues in the USA, have identified a biomarker which is strongly associated with triple negative breast cancer (TNBC), a highly aggressive carcinoma that often has early relapse and metastasis following chemotherapy. The newly identified biomarker, a gene called RASAL2, provides a target for developing new therapeutics designed to treat this often deadly disease.

TNBC is deadly because, unlike other types of breast cancers such as estrogen receptor (ER) positive or HER2 amplified breast tumours which have effective targeted therapy, TNBC tumours do not respond to targeted therapy.

Breast cancer has many subtypes, each with its own genetic makeup. As such, different subtypes behave differently in invasion and metastasis. Using breast cancer cell lines and genomic data from patient samples, molecular biologist Min Feng and her colleagues at the GIS adopted an integrated approach to search for genes whose deregulation may help explain the high metastatic potential of TNBC cells.

Dr Feng found that a small RNA, often called microRNA, is lost in highly metastatic TNBC cells but not in luminal breast cancer. As a result, RASAL2, which is negatively regulated by this microRNA, is up-regulated in a set of TNBC tumours. The study showed that TNBC patients whose tumours have high expression of RASAL2 tend to have a lower survival rate as compared to patients whose tumours have low levels of this gene. Additionally, the study showed that genetic knockdown of RASAL2 gene can lead to reduced metastasis in breast cancer mouse model.

The findings were published recently in the Journal of Clinical Investigation (JCI).

Intriguingly, previous research found that RASAL2 was lost in some of the luminal type of breast tumours, where it acts as a tumour suppressor.

Project leader of the study, Prof Qiang Yu, Senior Group Leader of Cancer Therapeutics and Stratified Oncology Programme at the GIS, said, "Cancer is an extremely heterogeneous disease, where many molecular processes have gone wrong in their own ways. Rather than a tumour suppressor, we show here that RASAL2 actually acts as a cancer promoting molecule in TNBC. This reminds us that the same molecule can function very differently in different subtypes of cancers, a phenomenon which has often been seen before."

The study is the result of intensive collaboration with both local and international colleagues, including Dr Ern Yu Tan at Tan Tock Seng Hospital, Singapore, and Dr Dave Hoon at the John Wayne Cancer Institute in Santa Monica, California.

Dr Tan, a breast cancer doctor, said, "Therapeutic options remain limited and women with TNBC have a higher risk of disease relapse, with prognosis being generally poor after a relapse. With this finding, RASAL2 could be a new potential biomarker that is associated with the high risk of TNBC, rather than all types of breast tumours. This illustrates an important aspect of breast cancer biology. With a better understanding of the genetic makeup of tumours, it is now recognized that breast cancer comprises a diverse mix of tumours. This explains why not everyone with tumours of the same disease stage responds the same way to similar treatment."

GIS Executive Director Prof Huck Hui Ng, said, "The study is a reflection of an adaptation of our efforts towards translational research. We are working hard to build up an ecosystem to allow close collaborations between researchers and clinicians. Because the laboratory findings do not always replicate the 'real world' of human tumours, validation with samples derived from actual human tumours remains the 'final proof' of whether novel laboratory findings can be applied to clinical practice."

Prof Yu emphasised the necessity of further clinical validation for the study. He is also seeking industrial collaboration to develop diagnostic assays for high risk TNBC patients.

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The research findings described in the media release can be found in the Journal of Clinical Investigation, under the title, "RASAL2 activates RAC1 to promote triple negative breast cancer progression" by Min Feng1, Yi Bao1, Zhimei Li1, Juntao Li2, Min Gong1, Stella Lam3, Jinhua Wang3, Diego M. Marzese3, Nicholas Donovan3, Ern Yu Tan4, Dave S.B. Hoon3, and Qiang Yu1,5,6

1Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, A*STAR, Biopolis, Singapore 138672
2Computational Biology, Genome Institute of Singapore, A*STAR, Biopolis, Singapore 138672
3Department of Molecular Oncology, John Wayne Cancer Institute, Santa Monica, CA 90404
4Department of General Surgery, Tan Tock Seng Hospital, Singapore 308433
5Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore 117597
6Cancer and Stem Cell Biology, DUKE-NUS Graduate Medical School of Singapore 169857

# Correspondence: yuq@gis.a-star.edu.sg

Ms Winnie Lim
Head, Office of Corporate Communications
Genome Institute of Singapore, A*STAR
Tel: +65 6808 8013
Email: limcp2@gis.a-star.edu.sg

The Genome Institute of Singapore (GIS) is an institute of the Agency for Science, Technology and Research (A*STAR). It has a global vision that seeks to use genomic sciences to achieve extraordinary improvements in human health and public prosperity. Established in 2000 as a centre for genomic discovery, the GIS will pursue the integration of technology, genetics and biology towards academic, economic and societal impact.

The key research areas at the GIS include Human Genetics, Infectious Diseases, Cancer Therapeutics and Stratified Oncology, Stem Cell and Regenerative Biology, Cancer Stem Cell Biology, Computational and Systems Biology, and Translational Research.

The genomics infrastructure at the GIS is utilised to train new scientific talent, to function as a bridge for academic and industrial research, and to explore scientific questions of high impact.

For more information about GIS, please visit: http://www.gis.a-star.edu.sg

The Agency for Science, Technology and Research (A*STAR) is Singapore's lead public sector agency that fosters world-class scientific research and talent to drive economic growth and transform Singapore into a vibrant knowledge-based and innovation driven economy.

In line with its mission-oriented mandate, A*STAR spearheads research and development in fields that are essential to growing Singapore's manufacturing sector and catalysing new growth industries. A*STAR supports these economic clusters by providing intellectual, human and industrial capital to its partners in industry.

A*STAR oversees 18 biomedical sciences and physical sciences and engineering research entities, located in Biopolis and Fusionopolis, as well as their vicinity. These two R&D hubs house a bustling and diverse community of local and international research scientists and engineers from A*STAR's research entities as well as a growing number of corporate laboratories.

For more information about A*STAR, please visit: http://www.a-star.edu.sg