{"entity": "publication", "iuid": "27cfaa66f25a41ca985fea1f860d6160", "timestamp": "2026-08-20T20:36:25.766Z", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/27cfaa66f25a41ca985fea1f860d6160.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/27cfaa66f25a41ca985fea1f860d6160"}}, "title": "Mechanical control of breast cancer malignancy by promotion of mevalonate pathway enzyme synthesis.", "authors": [{"family": "G\u00f6ransson", "given": "Sara", "initials": "S"}, {"family": "Olofsson", "given": "Helene", "initials": "H"}, {"family": "Johansson", "given": "Henrik J", "initials": "HJ"}, {"family": "Yan", "given": "Feifei", "initials": "F"}, {"family": "Vogiatzakis", "given": "Christos", "initials": "C"}, {"family": "Liang", "given": "Shuo", "initials": "S"}, {"family": "Bellato", "given": "Hermano Martins", "initials": "HM"}, {"family": "Masvidal", "given": "Laia", "initials": "L"}, {"family": "Aksoylu", "given": "Inci", "initials": "I"}, {"family": "Hartman", "given": "Johan", "initials": "J"}, {"family": "Hajj", "given": "Glaucia Nm", "initials": "GN"}, {"family": "Larsson", "given": "Ola", "initials": "O"}, {"family": "Lehti\u00f6", "given": "Janne", "initials": "J"}, {"family": "Str\u00f6mblad", "given": "Staffan", "initials": "S"}], "type": "journal article", "published": "2025-09-00", "journal": {"title": "Matrix Biol.", "issn": "1569-1802", "volume": "140", "pages": "1-15", "issn-l": "0945-053X"}, "abstract": "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.", "doi": "10.1016/j.matbio.2025.05.005", "pmid": "40516663", "labels": [], "xrefs": [{"db": "pii", "key": "S0945-053X(25)00050-2"}], "notes": [], "created": "2026-08-20T08:00:33.758Z", "modified": "2026-08-20T08:00:33.807Z"}