Targeting Metabolic Pathway May Halt Breast Cancer Progression

Mevalonate pathway associated with cell-signaling protein that promotes breast cancer development.

The mevalonate pathway (MVP) activates the cell-signaling protein Arf6 that promotes breast cancer progression, a recent study found.

The MVP metabolic pathway is up-regulated in certain breast cancers by the mutations in the tumor suppressor p53, allowing for enhancement in some cancer cell invasion and metastasis.

A study published in the Journal of Cell Biology found that MVP promotes the recruitment of Arf6 to the plasma membrane, where it is activated by receptor tyrosine kinases.

This process involves MVP generating a lipid group that anchors the protein Rab11b to cell membranes and allows for Rab11b to deliver Arf6 to its site of activation.

When Rab11b was inhibited it reduced the invasiveness of MDA-MB-231 — a breast cancer cell line – that expresses large amounts of Arf6.

Additionally, the Arf6 pathway could promote drug resistance in breast cancer cells. When Rab11b or a component of the Arf6 pathway called EPB41L5 were inhibited, it increased the sensitivity of MDA-MB-231 cells to 2 different cytotoxic compounds.

Arf6 signaling proteins are required for cancer cell metastasis and drug resistance.

Recently, statins that were originally developed to lower cholesterol levels have been examined as potential anti-cancer drugs, but clinical trials have produced mixed results in their efficacy.

However, researchers believe that statin-like drugs could be effective in treating breast cancer patients whose tumors have a high expression of Arf6. This is due to the ability of statins to inhibit the enzyme HMG-CoA reductase — one of the MVP’s key components – and could be susceptible to drugs that reduce Rab11b activity.

“Blocking the MVP might effectively kill cancer cells that overexpress the Arf6 pathway, especially in combination with other drugs,” said lead researcher Hisataka Sabe.

When simvastatin was injected into mice, researchers found that it increased the drug sensitivity of MDA-MB-231 cells and inhibited their ability to metastasize.