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Novel Cytochrome P45OlBl as a Mammary Cancer Risk Factor.

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Annual rept. 1 Jul 95-30 Jun 96,

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The research characterizes the role of cytochrome P4501B1 CYP1B1 as a contributor to breast cancer etiology. This enzyme may generate or remove a lipophilic hormone while also converting many environmental polycyclic aromatic hydrocarbons PAM to carcinogenic metabolites and estradiol E2 to potentially carcinogenic 4-hydroxy E2. This work now shows that CYP1B1 is the dominant constitutive activator of PAMs and E2 in human breast cells. Primary epithelial cultures from 7 normal human surgical samples all show constitutive CYP1B1 without the related CYP1Al form which metabolizes PAM. Addition of the environmental organochlorine compound dioxin elevates CYPiBi lOx while introducing CYPlAl. Constitutive expression of CYP1Bi and induction of CYPlAl varies 5-10 fold between cultures from different individuals apparently in proportion to variable expression of the Ah receptor which mediates dioxin effects. Studies with cultured human breast tumor cell lines indicate that loss of estrogen receptors decreases the ratio of CYPlAl to CYP1B1. Breast stromal fibroblasts express CYP1B1 stimulated by dioxin but not CYPlAl. Normal and tumor breast tissue consistently express CYP1B1 but not CYPlAl. The regulation of transcription of CYPIB1 has been studied in cultured rat mammary cells using promoter constructs. A gene region that mediates Ah receptordioxin regulation has been identified. However, environmental elevation of CYP1B1 is not a contributor relative to high basal expression which may however be subject to genetic variability.

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  • Medicine and Medical Research

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