SINGAPORE—Triple-negative breast cancer (TNBC) presents a host of challenges in treatment, as it tests negative for estrogen receptors, progesterone receptors and HER2. But the discovery of a new biomarker for this cancer type could provide fresh options for patients diagnosed with TNBC. Researchers at A*STAR’s Genome Institute of Singapore (GIS), collaborating with colleagues in the United States, have announced the identification of the gene RASAL2 as a biomarker strongly associated with triple-negative breast cancer. The study, titled “RASAL2 activates RAC1 to promote triple negative breast cancer progression,” appeared in the Journal of Clinical Investigation.
According to Breastcancer.org, approximately “10 to 20 percent of breast cancers, more than one out of every 10, are found to be triple negative.” This cancer type tends to be more aggressive and prone to metastasis, and as such, survival outcomes are generally poor. By working with breast cancer cell lines and genomic data from patient samples, the researchers used an integrated approach to identify genes whose deregulation could offer an explanation for the high metastatic potential of triple-negative breast cancer cells. Dr. Min Feng, a molecular biologist, and her colleagues at the GIS made the discovery that a microRNA is lost in highly metastatic TNBC cells, and as a result, RASAL2, which is negatively regulated by that microRNA, is upregulated in a set of TNBC tumors.
As noted in the paper’s abstract, RASAL2 “encodes a RAS-GTPase-activating protein (RAS-GAP), is a functional target of anti-invasive microRNA-203 and is overexpressed in a subset of triple-negative or estrogen receptor-negative (ER-negative) breast tumors.” Patients with TNBC whose tumors present with high expression of RASAL2 tend to have a lower survival rate compared to those with low levels of the gene in their tumors. Additionally, genetic knockdown of RASAL2 can result in reduced metastasis in breast cancer mouse models.
“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 tumors, validation with samples derived from actual human tumors remains the ‘final proof’ of whether novel laboratory findings can be applied to clinical practice,” GIS Executive Director Prof. Huck Hui Ng said in a press release.
The microRNA in question, though lost in TNBC, is not lost in luminal tumors. Additionally, previous research established the discovery that RASAL2 was lost in some luminal breast tumors, where it acts as a tumor suppressor. As defined by the Susan G. Komen website, “Most breast cancers are luminal tumors. Luminal tumor cells look the most like the cells of breast cancers that start in the inner (luminal) cells lining the mammary ducts.” There are luminal A and luminal B tumors, and both kinds tend to be estrogen receptor-positive and/or progesterone receptor-positive (luminal A tumors also tend to be HER2 negative). The paper’s authors note in the abstract that “As opposed to luminal B ER-positive breast cancers, in which RASAL2 has been shown to act as a RAS-GAP tumor suppressor, we found that RASAL2 is oncogenic in TNBC and drives mesenchymal invasion and metastasis. Moreover, high RASAL2 expression was predictive of poor disease outcomes in patients with TNBC.”
“Cancer is an extremely heterogeneous disease, where many molecular processes have gone wrong in their own ways,” said Prof. Qiang Yu, senior group leader of Cancer Therapeutics and Stratified Oncology Program at the GIS and project leader for this study. “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.”
“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. This illustrates an important aspect of breast cancer biology. 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,” said Dr. Ern Yu Tan of Tan Tock Seng Hospital, Singapore, a breast cancer doctor and collaborator on this study. Tan added that further clinical validation of these results is necessary.