Regulation of mevalonate pathway by Vav-Rac1 signaling favors breast primary tumorigenesis and lung metastasis

In the present study, we report that the expression of mevalonate pathway enzymes is mediated by the Rho guanosine nucleotide exchange factors Vav2 and Vav3 in a Rac1- and sterol regulatory element-binding factor-dependent manner in breast cancer cells. Furthermore, in vivo tumorigenesis experiments indicate that the two most upstream steps of this metabolic route (Hmgcs1, Hmgcr) are important for primary tumorigenesis, neoangiogenesis and cell survival in breast cancer cells. Hmgcr, but not Hmgcs1, is also important for the extravasation and subsequent fitness of breast cancer cells in the lung parenchyma. Genome-wide expression analyses revealed that Hmgcr influences the expression of gene signatures linked to proliferation, metabolism, and immune responses. The Hmgcr-regulated gene signature can predict long-term tumor recurrence but not metastasis in cohorts of non-segregated and chemotherapy-resistant breast cancer patients. The mevalonate pathway plays important roles in breast cancer and other tumor types. However, many issues remain obscure as yet regarding its mechanism of regulation and action. 4T1 cells were transduced with empty pLVX or pLKO lentiviral vectors (3 replicates included), lentiviral vectors expressing Hmgcr (3 replicates), and lentiviral shRNAs to Hmgcr (2 independent experiments, 3 replicates each).