Fluvastatin suppresses breast cancer initiation and progression via targeting CYP4Z1

Area of Science:

• Oncology
• Pharmacology
• Molecular Biology

Background:

• Breast cancer is a leading cause of cancer mortality in women worldwide.
• Identifying novel therapeutic targets and agents for breast cancer is a critical unmet need.
• Drug repurposing offers a strategy to accelerate the development of new cancer therapies.

Purpose of the Study:

• To identify FDA-approved CYP4Z1 inhibitors with anti-breast cancer activity using a drug repurposing approach.
• To evaluate Fluvastatin as a potential therapeutic agent targeting CYP4Z1 in breast cancer.
• To provide preclinical evidence for Fluvastatin's efficacy as an adjuvant therapy for breast cancer.

Main Methods:

• Molecular docking and site-directed mutagenesis were used to identify Fluvastatin as a CYP4Z1 inhibitor.
• In vitro studies assessed Fluvastatin's effects on breast cancer cell lines, including stemness, migration, invasion, and epithelial-mesenchymal transition.
• In vivo studies utilized xenograft and transgenic mouse models to evaluate Fluvastatin's impact on tumor growth, metastasis, and tumorigenesis.

Main Results:

• Fluvastatin was identified as a concentration-dependent inhibitor of CYP4Z1, binding to key active site residues.
• Fluvastatin treatment significantly reduced cancer stem cell properties, migration, invasion, and epithelial-mesenchymal transition in breast cancer cells.
• In vivo, Fluvastatin suppressed primary tumor growth and lung metastasis in xenograft models and delayed mammary tumor development in relevant transgenic mice.

Conclusions:

• Fluvastatin demonstrates significant anti-breast cancer activity through CYP4Z1 inhibition.
• This study validates Fluvastatin as a novel therapeutic candidate targeting CYP4Z1 for breast cancer treatment.
• Preclinical data support the potential of Fluvastatin in combination therapies for breast cancer.