Regulation of the Mevalonate Pathway in Breast Cancer and Its Role in Tumorigenesis and Lung Metastasis

Background Introduction

Breast cancer is one of the most common cancers among women worldwide, and its occurrence and metastasis mechanisms are complex, involving abnormal regulation of multiple signaling pathways and metabolic processes. In recent years, metabolic reprogramming has been recognized as a crucial mechanism for cancer cells to adapt to their rapid proliferation and metastatic needs. Among these, the mevalonate pathway has been found to be significantly upregulated in various cancers, particularly in breast cancer, where it is believed to play an important role in tumorigenesis and metastasis. However, the specific regulatory mechanisms of the mevalonate pathway and its functions in breast cancer remain incompletely understood.

The mevalonate pathway is a key metabolic route for the biosynthesis of cholesterol and isoprenoids in cells. The rate-limiting enzyme of this pathway is 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), whose activity is regulated by multiple signaling pathways, including the PI3K-AKT-mTORC1 pathway and the sterol regulatory element-binding factor (SREBF) family of transcription factors. Additionally, Rho GTPases and their guanine nucleotide exchange factors (GEFs) are also thought to play important roles in regulating the mevalonate pathway. However, how Vav family GEFs (particularly Vav2 and Vav3) regulate the mevalonate pathway in breast cancer, as well as the specific role of this pathway in tumorigenesis and metastasis, remains unclear.

Source of the Paper

This paper was co-authored by Javier Conde, Isabel Fernández-Pisonero, L. Francisco Lorenzo-Martín, and other researchers from multiple institutions in Spain, including the Centro de Investigación del Cáncer, Instituto de Biología Molecular y Celular del Cáncer, and CIBERONC (Centro de Investigación Biomédica en Red de Cáncer). The paper was published online on August 9, 2024, in the journal Molecular Oncology, with the DOI 10.¹⁰⁰²⁄₁₈₇₈-0261.13716.

Research Process and Results

1. Vav2 and Vav3 Regulate the Expression of Mevalonate Pathway Genes

The research team first discovered through gene expression analysis that Vav2 and Vav3 regulate the expression of all key enzymes in the mevalonate pathway in breast cancer cells. By knocking out the Vav2 and Vav3 genes, the researchers observed a significant downregulation of mevalonate pathway-related genes. Further experiments revealed that this regulation depends on the activity of the Rac1 GTPase and is closely associated with the activation of SREBF transcription factors. Using luciferase reporter assays, the researchers confirmed that Vav2 and Vav3 regulate the expression of mevalonate pathway genes through the Rac1-SREBF axis.

2. Role of HMGCS1 and HMGCR in Breast Cancer Primary Tumor Formation

To investigate the specific functions of the mevalonate pathway in breast cancer, the research team knocked out the HMGCS1 and HMGCR genes and observed their effects on breast cancer cells. The results showed that the knockout of HMGCS1 and HMGCR significantly inhibited the tumor-forming ability of breast cancer cells in vivo. Although these knockout cells showed little change in proliferation capacity in vitro, in mouse models, the tumors formed by HMGCS1 and HMGCR knockout cells were significantly smaller, and tumor angiogenesis and cell survival rates were also markedly reduced.

3. Role of HMGCR in Breast Cancer Lung Metastasis

Further research revealed that the knockout of HMGCR not only affected primary tumor formation but also significantly inhibited the lung metastasis ability of breast cancer cells. Through intravenous injection experiments, the researchers found that HMGCR knockout cells had a significantly reduced ability to colonize the lungs. Further experiments indicated that HMGCR knockout cells exhibited impaired extravasation and survival capabilities in the lungs. These results suggest that HMGCR plays a critical role in the lung metastasis process of breast cancer cells.

4. Gene Expression Programs Regulated by HMGCR

To elucidate the specific mechanisms of HMGCR in breast cancer, the research team conducted genome-wide expression analyses and identified a set of genes regulated by HMGCR (referred to as the “HMGCR-dependent gene signature”). These genes are closely related to processes such as cell proliferation, metabolic reprogramming, and immune responses. Further gene set enrichment analysis (GSEA) demonstrated that the HMGCR-dependent gene signature has prognostic value in breast cancer patients, particularly in predicting disease recurrence risk in chemotherapy-resistant patients.

Conclusions and Significance

This study revealed that Vav2 and Vav3 regulate the expression of mevalonate pathway genes through the Rac1-SREBF axis, thereby influencing tumorigenesis and lung metastasis in breast cancer cells. HMGCS1 and HMGCR, as key enzymes in the mevalonate pathway, play important roles in primary tumor formation and lung metastasis in breast cancer. Specifically, HMGCR not only affects tumor angiogenesis and cell survival but also plays a critical role in the lung metastasis process of breast cancer cells. Additionally, the discovery of the HMGCR-dependent gene signature provides a new molecular marker for prognostic assessment in breast cancer patients.

Research Highlights

1. Novel Regulatory Mechanism: This study is the first to reveal the molecular mechanism by which Vav2 and Vav3 regulate the mevalonate pathway through the Rac1-SREBF axis, providing new insights into metabolic reprogramming in breast cancer.
2. Dual Role of HMGCR: HMGCR not only plays a significant role in primary tumor formation in breast cancer but also plays a key role in lung metastasis, offering a theoretical basis for developing HMGCR-targeted therapies.
3. Discovery of Prognostic Markers: The identification of the HMGCR-dependent gene signature provides a new molecular marker for prognostic assessment in breast cancer patients, particularly in chemotherapy-resistant patients, with important clinical applications.

Other Valuable Information

This study also found that HMGCR knockout cells exhibit significantly increased sensitivity to ferroptosis, providing new insights for future development of ferroptosis-based breast cancer treatment strategies. Additionally, the HMGCR-dependent gene signature developed by the research team has prognostic value in breast cancer patients, offering potential molecular markers for personalized treatment.

This study not only elucidates the regulatory mechanisms of the mevalonate pathway in breast cancer but also provides new ideas and tools for breast cancer treatment and prognostic assessment.