Abstract
Epoxyeicosatrienoic acid (EET) production via cytochrome P450 (CYP) epoxygenases closely correlates with the progression of breast cancer. However, its role in the development of chemoresistant breast cancers has yet to be elucidated. Here, we found that CYP3A4 expression and its epoxy-product, 11,12-epoxyeicosatrienoic acid (11,12-EET) was enhanced in tamoxifen (TAM)-resistant MCF-7 (TAMR-MCF-7) breast cancer cells compared to control MCF-7 cells. Treatment of TAMR-MCF-7 cells with ketoconazole and azamulin (selective CYP3A4 inhibitors) or 14,15-epoxyeicosa-5(Z)-enoic acid (14,15-EEZE, an EET antagonist) inhibited cellular proliferation and recovered the sensitivity to 4-hydroxytamoxifen. Chick chorioallantoic membrane and trans-well migration analyses revealed that the enhanced angiogenic, tumorigenic, and migration intensities of TAMR-MCF-7 cells were also significantly suppressed by ketoconazole and 14,15-EEZE. We previously reported that Pin1, a peptidyl prolyl isomerase, is a crucial regulator for higher angiogenesis and epithelial-mesenchymal transition characteristics of TAMR-MCF-7 cells. EET inhibition suppressed E2F1-dependent Pin1 gene transcription, and Pin1 silencing also blocked cell proliferation, angiogenesis, and migration of TAMR-MCF-7 cells. Our findings suggest that the CYP3A4-mediated EET pathway represents a potential therapeutic target for the treatment of tamoxifen-resistant breast cancer.
Highlights
2 of 3 breast cancers require estrogen and functional estrogen receptor α (ER-α) for growth; anti-estrogens such as tamoxifen (TAM), a non-steroidal anti-estrogen, have been widely used and have been the most effective therapy in the treatment of ER-positive breast cancer patients [1]
Reverse transcriptase-polymerase chain reaction (RT-PCR) analysis revealed that the CYP3A4 mRNA level was dramatically increased in TAMR-MCF-7 cells compared to control MCF-7 cells, while CYP2C8 and CYP2C9 mRNA levels were only slightly enhanced, and the CYP2J2 mRNA level exhibited a decreasing trend (Figure 1A)
The pathological consequences of cancer are mainly correlated to tumor growth and metastasis, which are caused by uncontrolled cell proliferation, invasion, and migration
Summary
2 of 3 breast cancers require estrogen and functional estrogen receptor α (ER-α) for growth; anti-estrogens such as tamoxifen (TAM), a non-steroidal anti-estrogen, have been widely used and have been the most effective therapy in the treatment of ER-positive breast cancer patients [1]. CYP epoxygenases, including CYP2C8, 2C9, 2J2, and CYP3A4, have been well-known to convert AA to EETs [12,13,14]. The expression of these CYP epoxygenases has been reported to play a critical role in the tumorigenesis of diverse cancers, supporting a potential role for EETs in carcinogenesis. CYP2J2-derived EETs have been shown to promote invasion and metastasis in a variety of human cancers, including breast carcinoma [17]. The aim of this study was to identify the potential role of CYP epoxygenases and their derived EETs during the development of endocrine-resistant breast cancers
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