Mechanical control of breast cancer malignancy by promotion of mevalonate pathway enzyme synthesis.

Göransson S, Olofsson H, Johansson HJ, Yan F, Vogiatzakis C, Liang S, Bellato HM, Masvidal L, Aksoylu I, Hartman J, Hajj GN, Larsson O, Lehtiö J, Strömblad S

Matrix Biol. 140 (-) 1-15 [2025-09-00; online 2025-06-12]

In breast cancer, mechanotransduction from stiffened extracellular matrix (ECM) drives proliferation and invasion. Here, we use a model of matrix stiffening mimicking progression of breast ductal carcinoma in situ to invasive ductal carcinoma. Quantitative mass spectrometry identified enrichment of ECM-stiffness upregulated mevalonate pathway enzymes, indicating sterol/isoprenoid metabolism reprogramming. Consistently, the first committed mevalonate pathway enzyme, Hydroxymethylglutaryl-CoA Synthase (HMGCS1), was upregulated in human breast cancer specimens and spatially correlated with cross-linked ECM. ECM-stiffness promoted HMGCS1 protein synthesis without corresponding mRNA level alterations, indicating post-transcriptional regulation of mevalonate biosynthesis via microenvironmental mechanical cues to impose rapid metabolic alterations. Moreover, HMGCS1-RNAi blocked the stiffness-driven breast cancer proliferative and invasive phenotype. Mechanistically, mechanotransduction signaling, through integrin and Rac1 to promote HMGCS1 protein expression, drives the breast cancer malignant phenotype. Intriguingly, the Rac1-P29S cancer mutant promoted a malignant phenotype without stiff ECM in a mevalonate-dependent manner. In summary, we define a mechano-responsive pathway controlling mevalonate pathway enzyme synthesis that drives breast cancer malignant behaviors.

PubMed 40516663

DOI 10.1016/j.matbio.2025.05.005

Crossref 10.1016/j.matbio.2025.05.005

pii: S0945-053X(25)00050-2