Epithelial ovarian cancer derived from the human ovarian surface epithelium (HOSE) is the leading cause of death from gynecologic
malignancies among American women. Metabolic activation of endogenous and exogenous chemicals by
cytochrome P450 (CYP) class I
enzymes has been implicated in its etiology. In this study, we showed overexpression of
CYP1A1 mRNA, but not CYP1B1 transcripts, in
ovarian cancer cell lines when compared with primary cultures or immortalized HOSE cell lines. Importantly, we identified a novel, enzymatically active, spliced variant of
CYP1A1 (CYP1A1v) formed by excision of an 84-bp cryptic intron in exon 2. CYP1A1v is overexpressed in
ovarian cancer cell lines and exhibits a unique subcellular distribution restricted to the nucleus and mitochondria, contrary to the endoplasmic reticulum localization of the wild-type
enzyme. In concordance, total
CYP1A1 activity, as measured by the
ethoxyresorufin O-deethylase assay, was detected in mitochondrial, nuclear, and microsomal fractions of
ovarian cancer cells but was notably absent in all subcellular fractions of HOSE cells. Immunocytochemistry studies in 30 clinical specimens revealed overexpression of
CYP1A1 in various types of
ovarian cancers compared with benign epithelia and frequent localization of the
enzyme to
cancer cell nuclei. Forced expression of CYP1A1wt or CYP1A1v in HOSE cells resulted in nuclear localization of the
enzyme and acquisition of anchorage-independent growth, which was further exacerbated following exposure to
benzo(a)pyrene or 17beta-estradiol. Collectively, these data provided the first evidence that
CYP1A1 overexpression and alternative splicing could contribute to
ovarian cancer initiation and progression.