There and Back Again: A Perspective on 20 Years of CYP4Z1

Cytochrome P450 (CYP)4Z1, a highly expressed CYP gene in breast cancer, was one of the last CYPs to be identified in the human genome, some 20 years ago. CYP4 enzymes typically catalyze ω-hydroxylation and metabolize ω3 and ω6 polyunsaturated fatty acids to bioactive lipid metabolites that can influence tumor growth and metastasis. These attributes of CYP4Z1 make it an attractive target for new chemotherapeutic drug design, as a potential biomarker for selection of patients that might respond favorably to drugs and for developing enzyme inhibitors as potential therapeutic agents. This review summarizes the current state of knowledge regarding the advancing biochemistry of CYP4Z1, its role in breast cancer, and the recent synthesis of selective chemical inhibitors of the enzyme. We identify gaps that need to be filled to further advance this field and present new experimental data on recombinant CYP4Z1 expression and purification of the active catalytic form. SIGNIFICANCE STATEMENT: In breast cancer, an unmet need is the availability of highly effective therapeutic agents, especially for triple negative breast cancer. The relevance of the work summarized in this mini-review is that it identifies a new potential drug target, CYP4Z1, and discusses ways in which the gene product's catalytic activity might be modulated in order to combat this malignancy and limit its spread.