# Fluvastatin suppresses breast cancer initiation and progression via targeting CYP4Z1

## TL;DR

Fluvastatin, a drug repurposed from statins, shows potential to inhibit breast cancer growth and metastasis by targeting the CYP4Z1 enzyme.

## Contribution

Fluvastatin is identified as a novel CYP4Z1 inhibitor with anti-breast cancer activity through drug repurposing and preclinical validation.

## Key findings

- Fluvastatin inhibits CYP4Z1 by binding to key residues in its active site.
- Fluvastatin reduces cancer stem cell properties and epithelial-mesenchymal transition in breast cancer cells.
- Fluvastatin suppresses tumor growth and metastasis in xenograft and transgenic mouse models.

## Abstract

Breast cancer ranks highest globally in terms of both incidence and mortality rates among female malignancies. Elucidating the molecular mechanisms driving breast cancer initiation and progression, as well as identifying novel therapeutic agents, remains a critical unmet medical need. This study aimed to identify FDA-approved CYP4Z1 inhibitors with anti-breast cancer activity through a drug repurposing strategy, thereby providing preclinical evidence for potential clinical adjuvant therapies. Fluvastatin was identified as a concentration-dependent CYP4Z1 inhibitor through molecular docking and site-directed mutagenesis studies, binding to critical residues Lys109, Pro444, and Arg450 in the enzyme’s active site. Functional studies demonstrated that Fluvastatin significantly attenuated cancer stem cell properties, migratory/invasive capacities, and epithelial-mesenchymal transition in breast cancer cell lines. In vivo experiments revealed that fluvastatin suppressed primary tumor growth and lung metastasis in xenograft models, while delaying mammary tumorigenesis in PyMT-MMTV-CYP4Z1 transgenic mice. Notably, this effect was less pronounced in PyMT-MMTV wild-type controls. This study establishes Fluvastatin as a novel CYP4Z1-targeted therapeutic candidate for breast cancer, providing preclinical validation for its potential use in combination therapies.

A drug repurposing strategy identified fluvastatin as a CYP4Z1 inhibitor with a potential to inhibit the initiation and metastasis of breast cancer in vitro and in vivo.