Luteolin sensitises drug-resistant human breast cancer cells to tamoxifen via the inhibition of cyclin E2 expression

• Up to 50% of luminal type A breast cancer patients with metastatic disease do not respond to TAM.
• Cyclin E2 was expressed at higher levels in tamoxifen (TAM)-resistant breast cancer cells (4.89-fold, ∗P = 0.005).
• The cyclin E2 protein expression levels were inhibited in luteolin-treated (5 μM) TAM-resistant cells.
• Co-treated with 4-OH-TAM (100 nmol/L) and luteolin (5 μM) synergistically sensitised TAM-R cells to 4-OH-TAM.
• Targeting cyclin E2 expression by luteolin is useful to overcome TAM resistance in breast cancer patients.

Luteolin is a flavonoid that has been identified in many plant tissues and exhibits chemopreventive or chemosensitising properties against human breast cancer. However, the oncogenic molecules in human breast cancer cells that are inhibited by luteolin treatment have not been identified. This study found that the level of cyclin E2 (CCNE2) mRNA was higher in tumour cells (4.89-fold, ∗P = 0.005) than in normal paired tissue samples as assessed using real-time reverse-transcriptase polymerase chain reaction (RT-PCR) analysis (n = 257). Further, relatively high levels of CCNE2 protein expression were detected in tamoxifen-resistant (TAM-R) MCF-7 cells. These results showed that the level of CCNE2 protein expression was specifically inhibited in luteolin-treated (5 μM) TAM-R cells, either in the presence or absence of 4-OH-TAM (100 nM). Combined treatment with 4-OH-TAM and luteolin synergistically sensitised the TAM-R cells to 4-OH-TAM. The results of this study suggest that luteolin can be used as a chemosensitiser to target the expression level of CCNE2 and that it could be a novel strategy to overcome TAM resistance in breast cancer patients.