Triple-negative breast cancer, which is characterized by rapid recurrence and limited available targeted therapies, is considered the most difficult type of breast cancer to treat, often referred to as 'aggressive breast cancer.' However, in this type of breast cancer, a single gene was found to simultaneously inhibit the growth and metastasis of cancer cells while also promoting the phagocytic function of macrophages against cancer cells. These effects were confirmed separately in cultured cells, patient tissues, and mouse (rat) experiments.
A research team led by Kim Hyo-soo from the Institute of Life Sciences at Seoul National University Hospital and Lee Eun-ju (Prof.) (Park Hyo-min (Dr.)) from the Department of Biomedical Science announced on the 9th that they modified TIF1γ (TIP one gamma), a gene naturally present in the body, delivered it to preclinical models of triple-negative breast cancer, and confirmed its multi-target anti-cancer effects.
The research findings were published in the latest issue of the international academic journal 'Signal Transduction and Targeted Therapy.'
Triple-negative breast cancer is a type of breast cancer in which estrogen receptors, progesterone receptors, and Human Epidermal growth factor Receptor 2 (HER2) are all not expressed. It accounts for approximately 20% of all breast cancers, with rapid recurrence and a high tendency to spread to other organs. Due to the limited availability of targeted therapies, treatment primarily relies on chemotherapy.
Even targeted therapies have limitations. Existing targeted therapies that block only a single signal can be circumvented by cancer cells activating bypass signals to evade the blocking effect.
TIF1γ, which the research team focused on, is a protein that regulates various cellular signals, and reduced expression of this gene is common in cancers. The team revealed in 2020 that TIF1γ inhibits liver fibrosis and developed 'smart gene therapy' technology in 2022 that activates this gene only in diseased livers. In 2025, the scope was expanded to pulmonary fibrosis, and it has now been extended to cancer. This study used a gene (opti-hTIF1γ) with an optimized codon sequence designed to increase protein production within cells.
The research team cultured tumor tissues from seven triple-negative breast cancer patients at Seoul National University Hospital and delivered this gene into them. In the cancer cells that received the gene, vimentin, a protein associated with metastatic potential, and Ki67, a proliferation marker, decreased significantly, while cell death increased. The two markers also decreased in patient cancer cells that had spread outside the tissue. When the same experiment was conducted using mouse tumor tissues, the number of cancer cells spreading outside the tissue decreased by 70%.
The difference was also clear in mouse experiments. Human triple-negative breast cancer cells were transplanted into the breasts of mice, and 14 days later, lipid capsules (liposomes) containing the gene were injected around the tumors. By the end of the experiment, control group tumors had grown to over 300 square millimeters, whereas treatment group tumors were much smaller or nearly invisible. The area occupied by proliferating cancer cells (Ki67-positive area) also decreased to less than 10% of that in the control group.
Differences were observed in metastasis as well. Injected cancer cells were found in the lymph nodes of the control group but not in the treatment group. The lungs of the control group showed severe destruction of alveolar structure due to cancer lesions, while the lungs of the treatment group maintained normal structure. In another metastasis model where cancer cells were directly injected into breast mammary ducts, cancer cells pre-treated with the gene did not produce noticeable lung metastasis lesions.
Unlike existing methods that block only a single signal, TIF1γ showed a 'multi-target' effect by simultaneously inhibiting three key signaling pathways involved in cancer progression. In cultured triple-negative breast cancer cells, TIF1γ first induced the degradation of β-catenin protein, which promotes cancer growth and movement; second, it inhibited TGFβ signaling, which facilitates metastasis; and third, it degraded STAT3 protein, which aids in cancer cell survival and immune evasion.
Changes were also observed in the immune environment. In patient-derived cancer cells that received the gene, both the immune evasion protein (CD47) that cancer cells use to avoid macrophage attacks and the substance (CXCL5) involved in the influx of tumor-supporting macrophages decreased simultaneously. The research team believes that STAT3 inhibition is involved in this change.
The response of macrophages also changed. In macrophages co-cultured with cancer cells showing reduced CD47 and CXCL5 levels, receptors (SLAMF7) that promote phagocytosis increased. Furthermore, when cancer cell lines were co-cultured with macrophages, the gene-treated cancer cells were either engulfed or killed by the macrophages. In patient tissue cultures, fragments of cancer cells were observed inside macrophages. The research team named these macrophages, which have regained the ability to engulf cancer cells, 'tumor-targeting macrophages.'
This study is a preclinical trial, and the research team plans to continue follow-up studies, including developing delivery technologies that can be used for cancers that have spread systemically, in order to apply the findings to actual patients in the future.
Kim Hyo-su (Prof.) (Cardiovascular Research Group) stated, "While existing targeted therapies only blocked a single signal, this study confirmed that TIF1γ alone can simultaneously inhibit multiple signals involved in cancer cell growth and metastasis and restore the phagocytic function of macrophages against cancer cells," adding, "It presented the possibility of multi-target gene therapy that targets both the cancer cells themselves and the tumor microenvironment."
in THEBIO
