Targeting estrogen-mediated CYP4F2/CYP4F11-20-HETE metabolic disorder decelerates tumorigenesis in ER+ breast cancer

Abstract

Abstract Background The female hormone estrogen (E2) is essential for mammary gland development and unequivocally drives 80% of breast malignancies. The elucidation of molecular events in the E2-estrogen receptor (ER) α signaling pathway in ER + BC progression is of major scientific and therapeutic importance. Methods Lipid metabolomics profiling was used to examine the membrane phospholipid stimulated by E2. Clinical BC samples were used to assess the association of CYP4F2, CYP4F11 expression with clinicopathological characteristics and patient outcomes. ER + and ER- BC cells were used to examine the positive correlation between E2-ERα and CYP4F2, CYP4F11. Some Inhibitors of main enzymes in AA metabolism were used combined with E2 to assess roles of CYP4F2/CYP4F11 in the progression of ER + BC. CYP4F2, CYP4F11 overexpression and knockdown BC cell lines were employed to examine the effects of CYP4F2, CYP4F11 on cellular proliferation, apoptosis and tumor growth. Western blotting, qPCR, Immunohistochemical staining and flow cytometry were also conducted to determine the underlying mechanisms related to CYP4F2, CYP4F11 function. Results The activation of the CYP450 signaling pathway in arachidonic acid metabolism contributed to ER + BC tumorigenesis. In ER + BC, CYP4F2 and CYP4F11 overexpression induced by E2 could promote cancer cell proliferation and resistance to apoptosis by producing the metabolite 20-HETE and activating the antiapoptotic protein Bcl-2. CYP4F2 and CYP4F11 elevation correlates with poorer overall survival and disease-free survival in ER + BC patients. Conclusion CYP4F2, CYP4F11 and their metabolite 20-HETE could serve as effective prognostic markers and attractive therapeutic targets for novel anticancer drug development about ER + BC.