Molecular and epidemiological analyses of abnormal expression of aromatase in breast cancer.

One-third of human breast cancers exhibit estrogen-dependent proliferation. It appears that estrogen functions as a mitogenic factor in these carcinomas. As aromatase is the rate-limiting enzyme in estrogen biosynthesis. It could play an important role in the pathogenesis of estrogen-dependent breast cancer. The aromatase gene consists of at least six exons 1, each containing a promoter, and the tissue-specific expression is regulated by alternative use of these multiple promoters. The expression of aromatase in the breast and abdominal adipose tissues is regulated by a promoter flanking exon 1b. Molecular and epidemiological analyses of tissue-specific utilization of multiple exons 1 and promoters revealed a switching from use of the adipose-specific exon 1b to exon 1c in adipose tissues adjacent to the carcinomas in most breast cancer patients. Exon 1c has been shown to be specific for the ovary. Aromatase mRNA in adipose tissues distal to the tumour of the same patients was normally transcribed from exon 1b as was breast tissue in healthy controls. It is noteworthy that a switching from exon 1b to exon 1c was often observed in breast cancer patients having metastatic lymph nodes. These data suggest that switching from an adipose-specific exon 1b to exon 1c could cause a deviation from strict regulation of tissue-specific expression of the adipose aromatase leading to over-expression of the adipose aromatase. Consequently overproduction of local estrogen may promote carcinogenesis or proliferation of breast cancer cells.