Based on experimental and epidemiological evidence it is hypothesized that estrogen increases breast cancer risk by increasing mitotic activity in breast epithelial cells. Aromatase is crucial to the biosynthesis of estrogens and may therefore play a role in breast cancer development. Supporting data for an etiological role of aromatase in breast tumor biology are several-fold. First, the association between weight and postmenopausal breast cancer risk may be mediated by aromatase. Secondly, a pilot study found a higher aromatase expression in normal breast adipose tissue from breast cancer cases as opposed to healthy women. Thirdly, experimental data in animals suggest 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 androstenedione (E1/A) ratio in different ethnic groups was associated with ethnic differences in breast cancer incidence, and (ii) whether genetic variation in the CYP19 gene encoding the P450 aromatase protein was associated with breast cancer risk. The age-and weight-adjusted ethnic specific E1/A ratios ×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 high 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 intronic (TTTA) n repeat polymorphism with breast cancer risk in different ethnic groups. This polymorphism was not associated with differences in the plasma E1/A ratio in a way that would predict its functional relevance. We describe a newly identified TTC deletion in intron 5 of the CYP19 gene that is associated with the (TTTA) n repeat polymorphism. Neither this polymorphism, nor a polymorphism at codon 264 in exon VII of the CYP19 gene, was associated 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 I.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 Endocrine-Related Cancer (1999) 6 165-173 potential use of aromatase inhibitors as breast cancer chemopreventives depends on these results.

in 1981 were estimated to be taking ji blockers,' but nearly all of them would have to have survived because of fl blockade for this to account solely for the increased survival rates; this is unlikely given the modest effect on survival of j i blockers taken after infarction. 12

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We conducted an epidemiologic case-control study of thyroid cancer in women aged 40 and under to test the hypothesis that endogenous hormones may relate to the development of this disease, since the only known cause of thyroid cancer, ionizing radiation, does not account for the striking female over male excess. When compared to neighbour controls women with thyroid cancer more often had a history of benign hyperplastic thyroid disease (Relative Risk (RR) = 14.5; P less than 0.01) and more often had ever been pregnant (RR = 2.1; P = 0.04). Both these findings were consistent with findings of previous studies. After eliminating women with a history of hyperplastic thyroid disease from the analysis we found a strong association with miscarriage as the outcome of the first pregnancy (RR = 11.5; P less than 0.01), and we suspect that this factor may be another indicator of thyroid abnormality. An independent and increasing risk was observed with an increase in the total number of pregnancies after excluding women with prior thyroid disease and those whose first pregnancy ended in a miscarriage. The RR for 4 or more pregnancies was 6.3 (P = 0.03). Prior exposure to radiation therapy was not an important factor in our study of young women; this suggests that the emphasis in future studies of thyroid cancer must shift to study other types of risk factors.