Marker for aggressive breast cancer identified
Scientists at A*STAR’s Genome Institute of Singapore (GIS) 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.
The study documenting this finding has been published in the Journal of Clinical Investigation. TNBC is deadly because, unlike other types of breast cancers such as estrogen receptor (ER) positive or HER2 amplified breast tumors which have effective targeted therapy, TNBC tumors 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 Feng Min 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 tumors. The study showed that TNBC patients whose tumors have high expression of RASAL2 tend to have a lower survival rate as compared to patients whose tumors 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. Intriguingly, previous research found that RASAL2 was lost in some of the luminal type of breast tumors, where it acts as a tumor suppressor. Project leader of the study, Professor Yu Qiang, Senior Group Leader of Cancer Therapeutics and Stratified Oncology Program at the GIS, said, “Cancer is an extremely heterogeneous disease, where many molecular processes have gone wrong in their own ways.
Rather than a tumor 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. Tan Ern Yu 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 tumors.” “With a better understanding of the genetic makeup of tumors, it is now recognized that breast cancer comprises a diverse mix of tumors.
This explains why not everyone with tumors of the same disease stage responds the same way to similar treatment.” Prof. Yu emphasized the necessity of further clinical validation for the study. He is also seeking industrial collaboration to develop diagnostic assays for high risk TNBC patients
