Metabolomic Rewiring Promotes Endocrine Therapy Resistance in Breast Cancer.

Area of Science:

• Oncology
• Metabolic Research
• Molecular Biology

Background:

• Endocrine therapy resistance is a major challenge in estrogen receptor-positive (ER+) breast cancer, affecting approximately one-third of patients.
• Understanding resistance mechanisms is crucial for improving treatment outcomes.
• Mitochondrial fatty acid β-oxidation (FAO) is implicated in triple-negative breast cancer (TNBC) and Src signaling activation.

Purpose of the Study:

• To investigate metabolic reprogramming, specifically increased FAO, as a mechanism of endocrine therapy resistance in ER+ breast cancer.
• To identify therapeutic strategies to overcome endocrine resistance by targeting metabolic pathways and signaling cascades.

Main Methods:

• Integrated analysis of transcriptomic, metabolomic, and lipidomic data from TNBC cells to derive a gene signature.
• Molecular, genetic, and metabolomic experiments in ER+ breast cancer models (in vitro and in vivo).
• Assessment of carnitine palmitoyl transferase 1 (CPT1) inhibition, FAO inhibitors, and Src inhibitors.

Main Results:

• A TNBC-derived gene signature associated with FAO and CPT1 inhibition correlated with endocrine resistance in ER+ breast cancer patients.
• Endocrine therapy induced metabolic reprogramming, increasing FAO and activating AMPK-FAO-oxidative phosphorylation (OXPHOS) signaling in resistant ER+ breast cancer.
• CPT1 knockdown or FAO inhibitors enhanced endocrine therapy response; Src inhibitors suppressed resistant tumor growth, with synergistic effects when combined with CPT1 inhibition.

Conclusions:

• Metabolic reprogramming to increased FAO is a key mechanism driving endocrine therapy resistance in ER+ breast cancer.
• This FAO activation promotes resistance by upregulating the Src signaling pathway.
• Targeting both FAO (e.g., CPT1 inhibition) and Src signaling offers a promising therapeutic strategy to overcome endocrine resistance in ER+ breast cancer.