A metabolic pathway that is up-regulated in certain breast cancers promotes the disease's progression by activating a cell signaling protein called Arf6, according to a paper published in the Journal of Cell Biology. The study, "P53- and mevalonate pathway-driven malignancies require Arf6 for metastasis and drug resistance" by Ari Hashimoto and colleagues, has been published online ahead of print and suggests that statin-like drugs may be effective treatments for breast cancer patients whose tumors express high levels of Arf6 signaling proteins.

　　The mevalonate pathway (MVP) is a metabolic pathway that produces the building blocks for a wide range of biological molecules, from cholesterol to the long-chain lipid groups that anchor certain proteins to cell membranes. Mutations in the tumor suppressor p53 can up-regulate the MVP, a phenomenon that enhances the invasiveness of some, but not all, breast cancer cell lines. A team led by Hisataka Sabe at Hokkaido University Graduate School of Medicine in Sapporo, Japan, suspected that the MVP might promote invasiveness by activating the Arf6 signaling pathway, which enhances cancer cell invasion and metastasis by promoting the cells' transition to a more motile state.

　　Ari Hashimoto and colleagues found that the MVP promotes the recruitment of Arf6 to the plasma membrane, where it can be activated by receptor tyrosine kinases. The pathway does this by generating a lipid group that anchors a protein called Rab11b to cell membranes, allowing Rab11b to deliver Arf6 to its site of activation. Inhibiting Rab11b reduced the invasiveness of a breast cancer cell line, called MDA-MB-231, that expresses high amounts of Arf6 signaling proteins, the researchers discovered.

　　The Arf6 pathway may also boost the drug resistance of breast cancer cells, and Hashimoto et al. found that inhibiting Rab11b, or a component of the Arf6 pathway called EPB41L5, increased the sensitivity of MDA-MB-231 cells to two different cytotoxic compounds.

　　他汀类药物抑制HMG-CoA还原酶，这是MVP的关键成分之一。他汀类药物最初是为了降低胆固醇水平而开发的，它也被研究为潜在的抗癌药物，但迄今为止的临床试验结果好坏参半。Hashimoto等人的数据表明，未来的努力可能集中在肿瘤表达高水平Arf6信号蛋白的乳腺癌患者身上，因此这些患者可能对降低Rab11b活性的药物敏感。事实上，研究人员发现，当注射到小鼠体内时，辛伐他汀增加了MDA-MB-231细胞的药物敏感性，并抑制了细胞转移的能力。“阻断MVP可能会有效地杀死过度表达Arf6途径的癌细胞，特别是与其他药物联合使用时，”Sabe说。开发这种治疗方法可能是至关重要的，因为研究人员发现，肿瘤中表达高水平MVP成分和Arf6信号蛋白的患者的长期存活率很低。