I. Triple-Negative Breast Cancer: A Difficult Challenge in Breast Cancer Treatment
Triple-negative breast cancer (TNBC) represents the hardest-to-treat subtype of breast cancer, with a higher incidence among young women. The term "triple-negative" refers to the negative status of three core therapeutic targets for breast cancer: estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). The absence of these targets means there are no mature targeted therapies available; most patients can only receive chemotherapy, which yields limited overall efficacy and carries an elevated risk of tumour recurrence and metastasis.
Immunotherapy has broken the therapeutic deadlock in this field. On March 9, the FDA approved the PD-L1 antibody Tecentriq in combination with albumin-bound paclitaxel (Abraxane) as a first-line regimen for triple-negative breast cancer. Tecentriq thus became the first immunotherapy agent approved for TNBC. Meanwhile, a classic antihyperglycaemic drug has emerged in breast cancer research - metformin. On March 6, the research team led by Professor Marsha Rosner from the University of Chicago Comprehensive Cancer Center published a study in Nature. Using mouse models, they confirmed that combined treatment with metformin and heme could effectively suppress tumour growth in triple-negative breast cancer.
The study uncovered a potential anticancer mechanism by which metformin interferes with metabolic pathways in cancer cells, providing robust scientific evidence for repurposing an old drug. Although the research remains at the preclinical stage, its advantages of low cost and high safety profile attract extensive attention. With more clinical trials underway, metformin is expected to become an important supplement to the comprehensive treatment system for triple-negative breast cancer. It will offer patients more cost-effective therapeutic options, further enrich existing treatment modalities and improve patient prognosis.
II. Two Classic Repurposed Drugs: Metformin and Heme
The highlight of this research lies in the first investigation of combined antitumour therapy using two long-approved older drugs.
1.Metformin
Metformin was discovered in 1922 and formally introduced into clinical practice for type 2 diabetes mellitus in 1957. Its mechanism of action involves reducing hepatic glucose production and improving systemic insulin sensitivity. It ranked as the fourth most commonly prescribed drug in the United States in 2016. Multiple recent studies have verified that metformin exerts direct antitumour activity and inhibits the proliferation of tumour cells.
2.Heme
Heme was discovered even earlier. Scientists first isolated crystalline heme from blood in 1853. Clinically, it is mainly used to treat porphyria caused by defects in heme biosynthesis.
III. Core Target BACH1: A Key Regulator of Metabolism in Triple-Negative Breast Cancer
The research team identified transcription factor BACH1 as a core anticancer target and elucidated a novel molecular antitumour mechanism. BACH1 is highly expressed in triple-negative breast cancer cells and serves as a key protein driving tumour metastasis, primarily regulating mitochondrial metabolism. This protein binds to specific DNA sequences to modulate the rate of gene transcription and repress transcription of genes related to the mitochondrial electron transport chain.
Excess intracellular BACH1 disrupts normal energy supply in tumour cells. Importantly, BACH1 is not essential for cell survival. Pharmacological inhibition of this target does not trigger obvious toxic side effects, laying a solid foundation for safe medication application.
IV. Synergistic Mechanism of Combined Therapy and Results from Animal Experiments
The study proposed a complete logical framework for synergistic action: Treatment of tumour cells with heme downregulates BACH1 expression. Loss of BACH1 remodels metabolic pathways in tumour cells, and such metabolic reprogramming significantly enhances the antitumour effect of metformin, which subsequently inhibits mitochondrial respiration in cancer cells.
Hypotheses were validated in mouse models: the combination of heme and metformin markedly suppressed in vivo tumour growth in mice. The research confirmed that heme can boost tumour sensitivity to metformin. Principal investigator Professor Marsha Rosner pointed out: BACH1 is a critical regulator of mitochondrial metabolism and a core biomarker determining whether triple-negative breast cancer responds to metformin therapy.
V. Broad Application Prospects: Potential Extension to Multiple Malignancies
BACH1 expression is not limited to triple-negative breast cancer; it is detected in numerous malignant tumours including lung cancer, renal cancer, uterine cancer and prostate cancer. Based on this feature, the research team concluded that the antitumour strategy combining heme and metformin is not only applicable to triple-negative breast cancer. Future research may expand this regimen to more solid tumours, offering novel combination therapy ideas for multiple cancers.
