CYP4Z1 – A Human Cytochrome P450 Enzyme that Might Hold the Key to Curing Breast Cancer

Abstract

The human cytochrome P450 (CYP) enzyme CYP4Z1 is a fatty acid hydroxylase which among human CYPs is unique for being much stronger expressed in the mammary gland than in all other tissues. Moreover, it is strongly overexpressed in all subtypes of breast cancer, and some overexpression has also been found in other types of malignancies, such as ovarian, lung, and prostate cancers, respectively. Due to its unique expression pattern it is conceivable that this enzymes' activity might be exploited for a new therapeutic approach. However, the main challenge for a CYP4Z1-based prodrug strategy (CBPS) for the treatment of breast cancer (and possibly other CYP4Z1-positive malignancies) is the identification of candidate prodrugs that can be activated by this enzyme. In this mini-review we summarize the current knowledge about the enzymatic properties of the CYP4Z1 enzyme as well as on the expression pattern of the CYP4Z1 gene in both normal and cancer cells. Moreover, we present the first homology model of this enzyme and give an outlook on its potential use in cancer treatment strategies.

Anti-CYP4Z1 autoantibodies detected in breast cancer patients

“…As of now, an X-ray crystal structure of CYP4Z1 has not been reported; however, we recently published a homology model of this enzyme on the basis of the X-ray structure of human CYP3A4. 8 According to this model, residues His-198 to Leu-212 are all on the protein surface (Figure 1d), which supports the notion that this area is a target of anti-CYP4Z1 aAbs. There is still an urgent need to develop new diagnostic tools that allow for a sufficiently early diagnosis of breast cancer before it progresses to an often-incurable metastatic stage.…”

“…We recently published a homology model of CYP4Z1 on the basis of the X-ray structure of human CYP3A4 as a template. 8 The graph shows this structure with amino acids His-198 to Leu-212 highlighted in red.…”

Screening of cytochrome 4Z1 expression in human non-neoplastic, pre-neoplastic and neoplastic tissues

“…This enzyme is preferentially expressed in mammary tissues with undetectable levels in other normal human tissues. It was found to be overexpressed in different types of tumours as primary breast cancer tissues compared to their corresponding normal tissues [ 11 , 12 ]. Moreover, this expression was clarified to be inducible in glucocorticoids and progesterone-treated breast cancer cells [ 13 ].…”

“…Moreover, this expression was clarified to be inducible in glucocorticoids and progesterone-treated breast cancer cells [ 13 ]. In profiling the expression of CYP enzymes in breast, ovary and colon cancers, CYP4Z1 was overexpressed in all tumours examined compared to normal tissues, and its expression in ovary cancer was suggested to be a biomarker for prognosis [ 12 , 14 – 16 ]. Moreover, the elevated CYP4Z1 expression was correlated with a higher mortality rate in patients with prostate cancer and was suggested as an independent prognostic marker for prostate cancer [ 17 ].…”

WebHERV: A Web Server for the Computational Investigation of Gene Expression Associated With Endogenous Retrovirus-Like Sequences

“…CYP4Z1 is not expressed in all HL cell lines, so it seems unlikely that CYP4Z1 plays a major role in HL pathogenesis. Nevertheless, as recently discussed for breast cancer, CYP4Z1 might represent an interesting target for cancer therapy (Yang et al, 2017 ).…”