Of all the major breast cancer subtypes, triple-negative breast cancer (TNBC) has the worst prognosis and the lowest chance of long-term metastasis-free survival. Because it lacks the differentiated hormone receptors used as treatment targets in other breast cancer subtypes, TNBC lacks effective targeted therapies. That may soon change: researchers at Princeton University have found a therapeutic agent that launches a dual-pronged attack on TNBC, effectively suppressing its growth and metastasis in mouse models of the disease.
"People have tried to block the spread of this form of cancer, but attempts so far have failed because if you try one approach, the cancer cells compensate by finding a way to escape," commented the study's senior author, Yibin Kang, PhD, the Warner-Lambert/Parke-Davis Professor of Molecular Biology at Princeton University and Associate Director for Consortium Research at the Rutgers Cancer Institute of New Jersey. "With this new approach, the treatment blocks both pathways at the same time. It is like having one stone that kills two birds."
The study, published in Cancer Cell, introduces the therapeutic delivery of Tubulointerstitial nephritis antigen-like 1 (Tinagl1), a naturally occurring protein. This agent works by first binding directly to three receptors: the epidermal growth factor receptor (EGFR) and two integrins, αvβ1 and α5β1, also known as the fibronectin receptor. It then simultaneously inhibits the signaling pathways of focal adhesion kinase (FAK), which promotes tumor progression and metastasis, and EGFR, which promotes the formation of tumors. The interconnectedness of these two pathways contributes to the aggressiveness and treatment resistance associated with TNBC, so blocking them is particularly helpful to preventing the growth and spread of the disease.
In examining over 800 breast tumor samples from human patients, the researchers found that samples with higher levels of Tinagl1 tended to have good patient outcomes, whereas samples exhibiting less of this protein were associated with advanced tumor stages and shorter survival times. Of the various breast cancer subtypes, the effect of Tinagl1 levels on prognosis was strongest for tumor samples from patients with TNBC.
In mouse tumor cells engineered to express high levels of the Tinagl1 gene, the researchers found that increased Tinagl1 quantities resulted in slower growing tumors that were less likely to metastasize to the lung. Administering the Tinagl1 protein to mice with mammary tumors for seven weeks significantly slowed primary tumor growth and inhibited spontaneous lung metastasis without significant side effects. In another experiment, the investigators found that Tinagl1 was effective even after tumors had begun to metastasize.
Overall, the study authors conclude, Tinagl1 has strong potential as a therapeutic agent for TNBC.
For More Information
Shen M, Jiang Y, We Y, et al (2019). Tinagl1 suppresses triple-negative breast cancer progression and metastasis by simultaneously inhibiting integrin/FAK and EGFR signaling. Cancer Cell. [Epub ahead of print] DOI:10.1016/j.ccell.2018.11.016
Image credit: Wei Qian, University of Pittsburgh Cancer Institute. Courtesy of the National Cancer Institute