Researchers at Princeton University found that a compound called Tinagl1 blocks both the epidermal growth factor receptor (EGFR) and integrin pathways and slows the spread of triple-negative breast cancer.
The researchers found that Tinagl1 inhibits two major pathways that are helpful for the aggressiveness and drug resistance of triple-negative breast cancer. Tinagl1 can inhibit both pathways in different ways, overcoming the compensation mechanism for cancer evasion treatment.
On the one hand, Tingal1 blocks the activity of a tumor-promoting protein. Mutations in this protein-encoding gene cause the epidermal growth factor receptor gene (EGFR) to soar, send growth-promoting signals to cells, and promote tumor growth and spread. However, the treatment of targeted EGFR has limited clinical efficacy, probably because cancer cells have found new growth pathways.
On the other hand, Tingal1 can also act on integrins, which are involved in regulating cell migration. Cancer cells migrate to new regions through integrins, adhere to other cells, and transform into tumors. Tinagl1 is able to target integrin signaling by interfering with focal adhesion kinase (FAK), which promotes cell migration, growth and survival.
The researchers said that the two pathways are molecularly related and can compensate each other, contributing to the invasiveness and drug resistance of triple-negative breast cancer.
The research team observed more than 800 breast tumor samples collected from human patients. They found that tumor samples with low expression levels of Tinagl1 were more advanced in cancer and shorter in survival, while patients with higher Tinagl1 gene levels were better treated. This difference was most prominent in triple negative subgroup in breast cancer.
To test whether the Tinagl1 gene prevents tumor growth and spread, the researchers engineered human and mouse tumor cells to express high levels of the Tinagl1 gene. As a result, it was found that Tinagl1 was highly expressed in mouse cancer cells, tumor growth was slow, and these tumors were less likely to metastasize to the lungs.
The researchers also administered Tinagl1 protein to mice with breast tumors and found that treatment for 7 weeks significantly inhibited primary tumor growth and spontaneous lung metastasis without significant side effects. In an experiment on the timing of Tinagl1 treatment, Tinagl1 was still effective even with tumors beginning to metastasize. The researchers also analyzed the molecular mechanism of Tinagl1 inhibition and found that it inhibits EGFR and integrin/FAK signaling pathways, and therefore has a better therapeutic effect than using a single inhibitor (either against either of these two pathways).
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