ASSOCIATION OF CYTOCHROME-P450 1B1 (CYP1B1) POLYMORPHISM WITH STEROID-RECEPTOR STATUS IN BREAST-CANCER

A key enzyme involved in the production of potentially carcinogenic es trogen metabolites and the activation of environmental carcinogens is cytochrome P450 1B1 (CYP1B1), the predominant member of the CYP1 famil y expressed in normal breast tissue and breast cancer. Because of the preeminent role of CPP1B1 in mammary estrogen/carcinogen metabolism, w e examined the CYP1B1 gene to determine whether genetic differences co uld account for interindividual differences in breast cancer risk. We focused on exon 3, because it encodes the catalytically important heme binding domain of the enzyme, and discovered three polymorphisms of w hich two are associated,vith amino acid substitutions in codons 432 (V al-->Leu) and 453 (Asn-->Ser), designated as m1 and m2, respectively, Approximately 40% of Caucasian women have the m1 Val allele compared w ith nearly 70% of African-American women (P < 0.0001). The allele freq uency also differs significantly in m2 with the rare Ser allele being present in 17.4% of Caucasians but only in 3.4% of African Americans ( P < 0.0003). To determine whether the polymorphic CYP1B1 alleles hold implications as potential breast cancer risk factors, we compared the CYP1B1 genotypes in 164 Caucasian and 59 African-American breast cance r cases with those in age-, race-, and frequency-matched controls. Odd s ratio calculations failed to show a significant association between any of the genotypes and breast cancer. Because CYP1B1 is known to be involved in mammary estrogen metabolism, we investigated whether the e strogen receptor status is influenced by the CYP1B1 genotypes, Caucasi an patients with the m1 Val/Val genotype have a significantly higher p ercentage of estrogen receptor-positive (P = 0.02) and progesterone re ceptor-positive breast cancers (P = 0.003). There was no correlation w ith the m2 genotypes. These data suggest that the CYP1B1 polymorphisms in exon 3 are not associated,vith increased breast cancer risk but th at the mi polymorphism may be functionally important for steroid recep tor expression in breast cancer of Caucasian patients.