Biguanides antithetically regulate tumor properties by the dose-dependent mitochondrial reprogramming-driven c-Src...

Area of Science:

• Oncology
• Metabolic pathways
• Cancer signaling

Background:

• Metformin, a biguanide, is investigated for anti-cancer properties by attenuating mitochondrial oxidation.
• Clinical studies indicate metformin may increase proliferation and fatty acid β-oxidation (FAO) in a subset of breast cancer (BC) patients.
• FAO activation of Src kinase is implicated in aggressive triple-negative breast cancer (TNBC).

Purpose of the Study:

• To investigate the hypothesis that low-dose biguanide-driven signaling (AMPK-ACC-FAO) activates the Src pathway in TNBC.
• To explore the synergistic effects of biguanides, FAO inhibition, and Src inhibitors in TNBC models.

Main Methods:

• Utilized TNBC xenograft models to mimic low-dose metformin effects due to its low bioavailability.
• Assessed the impact of pharmacological and genetic inhibition of FAO on biguanide efficacy.
• Evaluated the combined effects of metformin and dasatinib (a Src inhibitor) on TNBC growth and metastasis.
• Investigated the influence of high-fat diet on the efficacy of the combination therapy.

Main Results:

• Pharmacological or genetic inhibition of FAO significantly enhanced the anti-tumor effects of biguanides.
• Lower doses of biguanides were found to induce Src signaling, while higher doses suppressed it.
• Metformin and dasatinib demonstrated synergistic inhibition of TNBC patient-derived xenograft growth, an effect not observed in high-fat diet-fed mice.
• The combination therapy also suppressed TNBC metastatic progression.

Conclusions:

• Low-dose biguanide-driven FAO signaling can activate the Src pathway in TNBC, potentially counteracting anti-tumor effects.
• Inhibiting FAO or combining biguanides with Src inhibitors offers a synergistic strategy to target metastatic TNBC.
• This combination therapy presents a promising approach for treating TNBC, particularly in patients with limited options.