Aromatase and breast cancer susceptibility

Based on experimental and epidemiological evidence it is hypothesized that estrogen increases breast cancer risk by increasing mitotic activity in bre ast epithelial cells. Aromatase is crucial to the biosynthesis of estrogens and may therefore play a role in breast cancer development. Supporting dat a for an etiological role of aromatase in breast tumor biology are several- fold. First, the association between weight and postmenopausal breast cance r risk may be mediated by aromatase. Secondly, a pilot study found a higher aromatase expression in normal breast adipose tissue from breast cancer ca ses as opposed to healthy women. Thirdly, experimental data in animals sugg est that aromatase activity predisposes mammary tissue to preneoplastic and neoplastic changes. In a multiethnic cohort study conducted in Los Angeles and on Hawaii we investigated (i) whether the plasma estrone to androstene dione (E1/A) ratio in different ethnic groups was associated with ethnic di fferences in breast cancer incidence, and (ii) whether genetic variation in the CYP19 gene encoding the P450 aromatase protein was associated with bre ast cancer risk. The age- and weight-adjusted ethnic specific E1/A ratios x 100 among women without oophorectomy were 7.92 in African-Americans, 8.22 in Japanese, 10.73 in Latinas and 9.29 in non-latina Whites (P=0.09). The h igh E1/A ratio in Latina women was not associated with a high breast cancer incidence; in fact Latina women had the lowest breast cancer incidence in the cohort observed so far. We found no consistent association of an intron ic (TTTA)(n) repeat polymorphism with breast cancer risk in different ethni c groups. This polymorphism was not associated with differences in the plas ma E1/A ratio in a way that would predict its functional relevance. We desc ribe a newly identified TTC deletion in intron 5 of the CYP19 gene that is associated with the (TTTA)(n) repeat polymorphism, Neither this polymorphis m, nor a polymorphism at codon 264 in exon VII of the CYP19 gene, was assoc iated with breast cancer. We did not identify any genetic variation in exon VIII in 54 African-American subjects. We identified rare genetic variants of unknown functional relevance in the promoter 1.4 of the CYP19 gene in 3 out of 24 Latina women. Further investigation into the role of aromatase in breast cancer etiology is important, given that the potential use of aroma tase inhibitors as breast cancer chemopreventives depends on these results.