A metabolic pathway that is upregulated in some breast cancers promotes disease progression by activating a specific cell signaling protein called Arf6, a study reported. But the researchers, working in a mouse model, also found that a lipid-lowering drug, simvastatin, inhibited metastasis, suggesting this statin class of medication can be an effective therapeutic approach in Arf6-expressing breast tumors.
The study, “P53- and mevalonate pathway–driven malignancies require Arf6 for metastasis and drug resistance,” was recently published in The Journal of Cell Biology.
The ADP-ribosylation factor 6 (ARF6) protein has a variety of cellular functions and is often overexpressed in tumors, promoting cell detachment (epithelial–mesenchymal transition) and invasiveness of healthy tissue. Such characteristics, coupled with drug resistance, are the building blocks of aggressive breast tumors. The metabolic mevalonate pathway (MVP), essential for the production of important molecules such as cholesterol and long-chain lipid groups, has also been associated with tumor invasiveness, but the molecular mechanisms behind this effect are unknown.
Researchers found that the MVP requires the Arf6 signaling pathway, promoting its recruitment to the plasma membrane, where Arf6 is activated. This process involves the generation of a lipid group that anchors a protein called Rab11b to cell membranes, allowing it to deliver Arf6 to its site of activation. Moreover, a known tumorigenesis promoter, called the mutant p53 protein, promotes Arf6 activation.
The team found that inhibiting Rab11b reduced the invasiveness of the MDA-MB-231 breast cancer cell line, which expresses high levels of Arf6 signaling proteins. This inhibition also increased the sensitivity of this tumor cell line to two different chemotherapy agents, suggesting the Arf6 pathway also promotes drug resistance in certain breast cancer cell lines. Importantly, overexpression of Arf6 and enhanced MVP activity correlated with poor patient survival.
Simvastatin, a drug belonging to the statin class, increased MDA-MB-231 cells’ drug sensitivity and inhibited metastasis in mice. This finding suggests that clinical trials testing the anti-cancer properties of statins, which are usually used to lower cholesterol but also block an enzyme essential to MVP, should continue and focus on breast cancers that express high levels of Arf6 signaling proteins.
“Blocking the MVP might effectively kill cancer cells that overexpress the Arf6 pathway, especially in combination with other drugs,” Dr. Hisataka Sabe, from the Hokkaido University Graduate School of Medicine in Sapporo, Japan, and the study’s lead researcher, said in a news release.