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Triple-negative breast cancer is notoriously difficult to treat as the tumors do not respond to hormone therapy or herceptin.

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Targeting triple-negative breast cancer

10 Mar 2020

A*STAR scientists have identified a microRNA that can potentially be targeted for the treatment of triple-negative breast cancer.

With advances in medicine, a cancer diagnosis is no longer regarded as a death sentence, especially if the disease is caught early. Yet, a one-size-fits-all treatment for cancer remains elusive because no two cancers are the same.

For instance, breast cancer alone has many subtypes. Hormone-sensitive breast tumors express estrogen and progesterone receptors which can be targeted by drugs mimicking the molecular shape of the two natural hormones. Another class of breast tumors with the HER2 protein on their surface can be treated with an antibody drug, Herceptin.

Meanwhile, some breast tumors express neither hormone receptors nor HER2. These tumors come under the category of triple-negative breast cancer (TNBC), and the prognosis for patients with TNBC tends to be poor due to the lack of available treatment options.

Instead of searching for druggable receptors on TNBC, researchers led by Prabha Sampath at A*STAR’s Skin Research Institute of Singapore (SRIS) screened triple-negative breast tumors for microRNAs, which are short sequences of nucleotides that regulate gene expression by binding to and destroying messenger RNA.

“We discovered that a microRNA species called miR-138 is expressed in TNBC but absent in healthy breast tissue and other types of breast tumors,” Sampath explained, adding that “the greater the abundance of miR-138, the lower are the chances of patient survival.”

Further experiments revealed that miR-138 blocks the production of the tumor suppressor protein TUSC2. Hence, when miR-138 expression is elevated, TUSC2 levels drop and TNBC cells divide more rapidly.

On the other hand, by blocking the activity of miR-138 in TNBC cells with an oligonucleotide (a short nucleotide strand that binds to and neutralizes miR-138), the researchers were able to inhibit cell division and induce programmed cell death. In mice, breast tumors depleted of miR-138 were also significantly smaller than breast tumors that expressed miR-138.

“The current mainstay for TNBC treatment is chemotherapy. As a critical microRNA required for cancer cell survival and growth, miR-138 is an attractive therapeutic target for combating TNBC,” Sampath said.

However, she noted that therapeutic oligonucleotides targeting microRNAs such as miR-138 must first withstand degradation, be delivered precisely to the tumor tissue, then be taken up efficiently by cancer cells. These are hurdles that Sampath and her team are looking to overcome.

“We have a patent application on the anti-miR-138 oligonucleotides, which we are developing for therapeutic use in TNBC and glioblastoma, an aggressive brain cancer,” she said.

The A*STAR-affiliated researchers contributing to this research are from the Skin Research Institute of Singapore (SRIS).

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References

Nama, S., Muhuri, M., Di Pascale, F., Quah, S., Aswad, L. et al. MicroRNA-138 is a Prognostic Biomarker for Triple-Negative Breast Cancer and Promotes Tumorigenesis via TUSC2 repression. Scientific Reports 9, 12718 (2019) | article

About the Researcher

Prabha Sampath

Senior Principal Investigator

Skin Research Institute of Singapore
Prabha Sampath obtained her PhD degree in molecular medicine from the Cleveland Clinic Foundation, US, in 2004. She is now a Senior Principal Investigator at A*STAR’s Skin Research Institute of Singapore (SRIS) and holds adjunct positions at the Yong Loo Lin School of Medicine, National University of Singapore (NUS), and the Duke-NUS Medical School. Her research interests include studying the molecular mechanisms underlying pathological conditions such as cancer and identifying specific novel therapeutic targets for those diseases.

This article was made for A*STAR Research by Wildtype Media Group