Long-term estrogen-deprived estrogen receptor α-positive breast cancer cell migration assisted by fatty acid 2-hydroxylase

The risk of breast cancer (BC) recurrence is high in postmenopausal women, though the underlying molecular mechanisms are not yet fully understood. We developed a long-term estrogen-deprived (LTED) cell line from MCF-7 cells, which we used as an in vitro model for aromatase inhibitor (AI)-resistant estrogen receptor α (ERα)-positive postmenopausal BC. We also describe the involvement of fatty acid 2-hydroxylase (FA2H) in the modulation of LTED cell migration. Small interfering RNA specific to FA2H (siFA2H) could reduce cell migration, whereas the introduction of plasmid expressing FA2H, but not its inactive mutant, resulted in enhanced migration. Moreover, proliferation of the LTED cells was not affected by modulation of FA2H expression. Fulvestrant (FUL), a selective estrogen receptor degrader used to treat AI-resistant ERα-positive postmenopausal BC, was found to induce degradation of ERα together with a decrease in ER-mediated transcription; however, FA2H protein expression and migration remained unchanged. Overall, the findings of this study suggest that FA2H is one of the drivers of LTED cell migration, and that LTED cells resistant to FUL therapy may be involved in malignancy and metastatic mechanisms.