UNMC researchers identify key protein in breast cancer brain metastasis

UNMC researchers have identified a key protein whose increased presence helps promote breast cancer brain metastasis, opening a new area of research into the dire condition.

In their recent findings, published in the journal Clinical Cancer Research, the research team found the MUC5AC protein is upregulated in patients whose cancer has spread to the brain.

The finding provides a rationale for developing a new predictive biomarker for brain metastasis in high-risk breast cancer patients. In addition, the researchers noted that the study offers a route to develop therapeutic targets for those cases.

Wasim Nasser, PhD, an associate professor in the UNMC Department of Biochemistry and Molecular Biology, said that the research also provides a potential platform to detect brain metastasis early in breast cancer patients.

Brain metastasis is an ominous complication that occurs in around 20-40% of patients with solid tumors diagnosed with breast cancer, lung cancer or melanoma, said Dr. Nasser, who served as lead researcher and corresponding author on the study.

But with few therapies available for the affected patients with breast cancer brain metastasis, the patients typically live only for about five to 10 months, Dr. Nasser said.

According to the publication, mucin proteins previously have been implicated in cancer progression, and the researchers sought to answer whether and how they might be involved in breast cancer brain metastasis.

The study established that the secretory protein MUC5AC, through its interaction with cMET and CD44v6 receptors, is critical for breast cancer brain metastasis. The researchers’ publication in Clinical Cancer Research is titled “Mucin 5AC Promotes Breast Cancer Brain Metastasis through cMET/CD44v6.”

“It is imperative to characterize the factors responsible for brain metastasis and develop targeted therapies to challenge this complication,” Dr. Nasser said.

The research team crossed five departments at UNMC, along with the Fred & Pamela Buffett Cancer Center, Eppley Institute for Research in Cancer and Allied Diseases and the UNMC Division of Oncology-Hematology in the UNMC College of Medicine. Researchers also collaborated with the VA-Nebraska Western Iowa Health Care System and the University of Colorado Comprehensive Cancer Center.

The work was supported by numerous grants from the National Institutes of Health and support from the Fred & Pamela Buffett Cancer Center, among other financial support.

Dr. Nasser is an associate member of the Fred & Pamela Buffett Cancer Center, a National Cancer Institute-designated cancer center.

Dr. Nasser, whose research specializes in understanding the complexities that are involved in the brain metastasis pathogenesis, said the research team was intrigued to find the drivers that were potential threats to causing brain metastasis.

After analyzing multiple datasets of patients with brain metastasis, Dr. Nasser said, the team found that mucins were dysregulated and MUC5AC specifically was among the top upregulated genes. The connection was particularly strong in breast cancer patients with the HER2-positive cancer subtype, he said, and led to lower survival rates.

Having established that connection, the researchers then worked with animal models. The researchers found that silencing MUC5AC in breast cancer brain metastatic cells for the experiment reduced brain metastasis in vivo.

In the study experiments, a cancer therapeutic already available for other uses – a cMET inhibitor known as Bozitinib, or PLB1001 – showed promise in inhibiting MUC5AC expression.

The study concluded that blocking MUC5AC and its axis with the cMET and CD44v6 proteins using a cMET inhibitor will be a novel therapeutic approach for breast cancer brain metastasis.

Dr. Nasser said the research team now is extending the study to other cancers that can metastasize to the brain, including lung cancer and melanoma. Researchers also are hoping to push the Bozitinib therapy for clinical trials, he said.