甲羟戊酸途径在乳腺癌和其他肿瘤类型中起着重要作用。然而,关于其监管和行动机制,许多问题仍然模糊。在本研究中,我们报道,在乳腺癌细胞中,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-和固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)]对于原发性肿瘤发生很重要,血管生成,和乳腺癌细胞中的细胞存活。HMGCR,但不是HMGCS1,对于肺实质中乳腺癌细胞的外渗和随后的适应性也很重要。全基因组表达分析显示,HMGCR影响与增殖相关的基因标记的表达,新陈代谢,和免疫反应。HMGCR调节的基因标签预测非隔离和化疗耐药乳腺癌患者队列中的长期肿瘤复发而非转移。这些结果揭示了一个迄今未知的,VAV催化依赖性机制参与调节乳腺癌细胞中的甲羟戊酸途径。他们还鉴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。
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.