Tackling triple-negative breast cancer by blocking 2 key survival pathways

Breast Cancer Cells
In mouse models of triple-negative breast cancer, the protein Tinagl1 blocked two cancer promoters, epidermal growth factor receptor and focal adhesion kinase. (National Cancer Institute)

Triple-negative breast cancer is the toughest form of the disease to treat because it lacks estrogen and progesterone receptors and it doesn’t overexpress HER2, making it unresponsive to targeted treatments. Now, a team of researchers led by Princeton University have promising early evidence that a recombinant protein could block two pathways triple-negative cancer cells use to grow and spread beyond the primary tumor.

The treatment, called Tinagl1, is inspired by a naturally occurring protein. When the researchers engineered human and mouse tumor cells to produce high levels of the protein, the cells formed slow-growing tumors that were less likely to metastasize.

They went on to test Tinagl1 in mice with mammary tumors and found the treatment inhibited cancer growth and lung metastasis, with no side effects. They reported their findings in the journal Cancer Cell.

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The researchers believe Tinagl1 impedes the action of the gene epidermal growth factor receptor (EGFR), which can fuel tumor growth when it becomes mutated. There are EGFR inhibitors on the market to treat cancer, but they’re not always effective because cancer cells can find other ways to grow, said Princeton molecular biology professor and lead author Yibin Kang in a statement.

Tinagl1 could offer an advantage in its ability to stop another process cancer cells use to ensure their survival. It interferes with another protein called focal adhesion kinase, which in turn inhibits integrins, molecules that regulate the ability of cancer cells to migrate and turn into tumors, according to the researchers.

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Finding new ways to exploit vulnerabilities in triple-negative breast cancer is a major focus of research. Last year, scientists at the Cleveland Clinic discovered a stem cell pathway that helps triple-negative tumors survive, and they proposed that blocking the highly expressed protein Cx26 could cripple this mechanism of cancer survival. A team of National Institutes of Health scientists is working to decode DHHC enzymes, which influence 1,000 human proteins, including cancer-causing EGFRs.

In their mouse study, the Princeton scientists saw encouraging evidence that the double punch delivered by recombinant Tinagl1 could help combat the ability of triple-negative breast tumors to persist. Even when they administered the treatment after metastases had already formed, it worked, they reported.