GGPS1 Gene Expression in Triple-Negative Breast Cancer: Impact on the Risk of Distant Metastasis and Potential Use as a Target for Therapy

Background: This in silico study aimed to investigate, in triple-negative breast cancers (TNBCs), the expression of genes involved in the production of geranylgeranyl-diphosphate (GGDP), an intermediate in the mevalonate/cholesterol pathway essential for the post-translational modification of the RhoA small GTPase, and their impact on distant-relapse-free survival (DRFS).

Methods: The study utilized a publicly available dataset to examine four genes (HMGCR, FDPS, FDFT1, and GGPS1) involved in the mevalonate/cholesterol pathway, as well as five essential components of the RhoA/ROCK signaling pathway: RHOA, ROCK1, LIMK1, MYL1, and CFL1. The impact of gene expression on DRFS was analyzed using the Cox regression model, with gene expression treated as continuous or categorical covariates.

Results: When stratified according to the optimal cutoff, the expression of GGPS1, RHOA, ROCK1, LIMK1, and CFL1 significantly affected the occurrence of distant metastasis. LIMK1 was associated with a 51% decreased risk of developing distant metastasis, whereas GGPS1, RHOA, ROCK1, and CFL1 were associated with a substantially increased risk (100%, 108%, 80%, and 89%, respectively). In basal-like 2 (BL2), the TNBC subtype known for its poor prognosis, tumors with high levels of GGPS1 were associated with a very short DRFS.

Conclusions: Given the crucial role of the RhoA small GTPase in activating the RhoA/ROCK pathway, preventing RhoA geranylgeranylation by inhibiting the expression of GGPS1 gene by statins or the activity of the enzyme by bisphosphonates and GGPS inhibitors could be a promising therapeutic strategy to enhance the limited effectiveness of the current taxane-based chemotherapy used to treat TNBCs.

Keywords: Triple-Negative Breast Cancer, Distant Metastasis, Ggps1 Gene, Rhoa/Rock Signaling Pathway.