Research Papers:

Role of the CYP3A4-mediated 11,12-epoxyeicosatrienoic acid pathway in the development of tamoxifen-resistant breast cancer

Nguyen Thi Thuy Phuong, Ji Won Kim, Jung-Ae Kim, Jang Su Jeon, Ji-Yoon Lee, Wen Jun Xu, Jin Won Yang, Sang Kyum Kim and Keon Wook Kang _

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Oncotarget. 2017; 8:71054-71069. https://doi.org/10.18632/oncotarget.20329

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Nguyen Thi Thuy Phuong1,*, Ji Won Kim1,*, Jung-Ae Kim2, Jang Su Jeon3, Ji-Yoon Lee3, Wen Jun Xu1, Jin Won Yang1, Sang Kyum Kim3 and Keon Wook Kang1

1College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, South Korea

2College of Pharmacy, Yeungnam University, Gyeongsan 38541, South Korea

3College of Pharmacy, Chungnam National University, Daejeon 34134, South Korea

*These authors have contributed equally to this work

Correspondence to:

Keon Wook Kang, email: [email protected]

Sang Kyum Kim, email: [email protected]

Keywords: tamoxifen resistance, CYP3A4, epoxyeicosatrienoic acid, migration, angiogenesis

Received: October 25, 2016     Accepted: June 27, 2017     Published: August 18, 2017


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.

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