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RESEARCH PRODUCT

The Elovl5 enzyme in breast cancer : regulation of cancer cell proliferation and metastasis

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Breast cancer is the most diagnosed cancer and the leading cause of cancer death in women. The 5-year relative survival rate is less than 30% for metastatic breast cancer and metastases account for more than 75% of breast cancer deaths. Fatty acid metabolism is altered in cancer and contributes to tumor progression and metastasis. Here, we were interested in Elongation of very long chain fatty acids protein 5 (Elovl5) which catalyzes the elongation of long-chain fatty acids. We observed that the tumors from patients with a breast cancer had a lower expression of Elovl5 than paired normal breast tissue. However, low expression of Elovl5 is associated with a worse prognosis in breast cancer patients with a luminal (ER+) or basal-like subtype. In accordance with this finding, we showed that the decrease of Elovl5 expression is more pronounced in ER+ breast tumors from patients with metastases in lymph nodes. Although Elovl5 downregulation limits breast cancer cell proliferation and cancer progression, we demonstrated that repression of Elovl5 expression promoted EMT and lung metastases in murine breast cancer models. A repression of Elovl5 expression in breast cancer cells led to an upregulation of TGF-β receptors mediated by an accumulation of lipid droplets which is suppressed by a blockade of triacylglycerol synthesis with pharmacological drugs inhibiting DGAT1/2. Interestingly, the abolition of Elovl5-regulated lipid droplet formation reversed the induction of TGF-β receptors, EMT and cell invasion. Altogether, we showed that Elovl5 expression is a predictive marker for the risk of metastases development in breast cancer and that Elovl5 regulated the metastatic process through modulation of the expression of TGF-β receptors mediated by lipid droplets.