甲羟戊酸途径在乳腺癌和其他肿瘤类型中发挥着重要作用。然而，其监管和作用机制仍存在许多问题。在本研究中，我们报道乳腺癌细胞中甲羟戊酸途径酶的表达是由 RHO 鸟苷核苷酸交换因子 VAV2 和 VAV3 以 RAC1 和甾醇调节元件结合因子 (SREBF) 依赖性方式介导的。此外，体内肿瘤发生实验表明，该代谢途径的两个最上游步骤[3-羟基-3-甲基戊二酰辅酶A合酶1（HMGCS1）和3-羟基-3-甲基戊二酰辅酶A还原酶（HMGCR）]是对于乳腺癌细胞的原发性肿瘤发生、血管生成和细胞存活很重要。 HMGCR（而非 HMGCS1）对于乳腺癌细胞在肺实质中的外渗和随后的适应性也很重要。全基因组表达分析表明，HMGCR 影响与增殖、代谢和免疫反应相关的基因特征的表达。在非隔离和化疗耐药的乳腺癌患者群体中，HMGCR 调节的基因特征可预测长期肿瘤复发，但不能预测转移。这些结果揭示了一种迄今为止未知的、VAV 催化依赖性机制，涉及乳腺癌细胞中甲羟戊酸途径的调节。他们还确定了导致乳腺癌细胞恶性特征的特定甲羟戊酸途径依赖性过程。© 2024 作者。约翰·威利出版的《分子肿瘤学》

The mevalonate pathway plays an important role in breast cancer and other tumor types. However, many issues remain obscure as yet regarding its mechanism of regulation and action. 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 (SREBF)-dependent manner in breast cancer cells. Furthermore, in vivo tumorigenesis experiments indicated that the two most upstream steps of this metabolic pathway [3-hydroxy-3-methylglutaryl-coenzyme A synthase 1 (HMGCS1) and 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR)] are important for primary tumorigenesis, angiogenesis, 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 predicts long-term tumor recurrence but not metastasis in cohorts of nonsegregated and chemotherapy-resistant breast cancer patients. These results reveal a hitherto unknown, VAV-catalysis-dependent mechanism involved in the regulation of the mevalonate pathway in breast cancer cells. They also identify specific mevalonate-pathway-dependent processes that contribute to the malignant features of breast cancer cells.© 2024 The Author(s). Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.