Tumor-initiating cells, thought to give rise to cancer, are often associated with treatment resistance and disease recurrence. Now researchers have identified a protein, called G3BP2, that is essential to the survival of these cells in breast cancers.
Targeting this protein with a chemical compound the researchers also identified effectively reduced the numbers of these cells in various breast cancer models, suggesting this approach may lower treatment resistance and improve outcomes for patients.
The study, “Stress Granule-associated Protein G3BP2 Regulates Breast Tumor Initiation,” was published in the journal Proceedings of the National Academy of Sciences (PNAS).
Tumor-initiating cells (TICs) are one of the many different types of cells seen in breast cancer. Although present in small amounts in breast and most other cancers, TICs are believed to give rise to all cancer cells within a tumor.
These cells play an important role in cancer survival because they resist standard anti-cancer therapies. But a better understanding of how these cells work is an essential first step in combatting them.
Using cultures of metastatic breast cancer cells containing a significant number of TICs, researchers tested the effectiveness of the chemotherapy drug Taxol (paclitaxel) combined with different compounds — more than 60,000 in all. Among the compounds tested, the drug C108 had the most pronounced effect in decreasing cancer cell survival.
They then tested this combination in other cultures of TIC-enriched breast cancer cells, and observed that C108 not only enhanced the toxic effects of Taxol, but also killed TICs when administered alone.
Next, the team tested C108 in mouse models of breast cancer, and found the proportion of TICs reduced by nearly 10-fold in treated mice, compared to mice given placebo.
Molecular experiments showed that C108 acts by inhibiting a protein called G3BP2. This protein is present in stress granules, which are cellular structures that protect RNA molecules from stresses like chemotherapy drugs.
Using samples from more than 4,000 breast cancer patients, researchers also observed that G3BP2 levels correlated with increased treatment resistance and with metastasis. G3BP2 works by controlling the levels of TICs within breast tumors, promoting the pluripotency of cancer cells (their ability to give rise to other cell types) by increasing the expression of proteins related to their stem cell-like factors, called Oct-4 and Nanog.
“The protein we have identified — G3BP2 — affects the survival and proliferative potential of breast cancer cells by regulating the ratio of TICs to non-TICs within a tumor,” Igor Garkavtsev, MD, PhD, the study’s senior author, said in a news release. “We also found that G3BP2 regulates breast tumor initiation in a way that leads to the increased expression of Oct-4 and Nanog, contributing to the pluripotency of embryonic stem cells.”
“The possibility that some breast cancer cells with vast proliferative potential may be intrinsically resistant to standard therapies may partially explain why tumors relapse after treatment,” he added. “Our identification of compound C108 and the discovery of G3BP2 as a potential regulator of TICs open opportunities for further exploration of the mechanisms of breast cancer initiation and the development of novel therapies.”
Specifically, Garkavtsev said, “[c]ombining derivatives of compound C108 with standard treatments could benefit patients with relapsed, drug-resistant or metastatic breast cancer and improve their survival.”
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