In the human, estrogens are synthesized in a number of tissue sites including ovarian granulosa cells and corpus luteum, placental syncytiotrophoblast, various sites in the brain, as well as adipose tissue. Estrogen biosynthesis in adipose tissue increases not only with obesity but also with age. Its physiological significance is unclear, but from a pathophysiological standpoint it has been implicated in a number of human diseases, notably endometrial cancer and breast cancer. In order to study the regulation of estrogen biosynthesis we have cloned and characterized the gene encoding human aromatase cytochrome P450 (P450arom), the enzyme responsible for estrogen biosynthesis. We have found that this gene exceeds 70 kb in length and that its tissue-specific expression is regulated by the use of alternative promoters. In the ovary expression is regulated by a promoter proximal to the translational start site (promoter II). In the placenta, expression is regulated by a promoter which is at least 40 kb upstream from the start of translation (promoter I.l). In adipose tissue in situ, expression is regulated by a third promoter (1.4) whose position within the gene has yet to be ascertained. Unexpectedly, when human adipose stromal cells are placed in culture, promoter selection appears to be dictated by the culture conditions, namely the presence or absence of cAMP, dexamethasone and growth factors. In order to study the molecular and cellular mechanisms responsible for this novel regulation of gene expression, we propose to characterize the regulatory elements present in regions of the gene upstream of each of the promoters which drive expression in adipose stromal cells, as well as in situ. The transcription factors which interact with these genomic regulatory elements will be characterized and their role in hormonal and tissue-specific regulation defined. In particular, we wish to determine the role of growth factors in switching promoter use in cells in culture. We will also seek to establish whether transcriptional activation or inhibition per se is sufficient to determine the switching of promoter use or whether additional mechanisms are required, such as the regulation of alternative splicing factors which determine the preferential employment of specific 5'-splice sites. Lastly, we will determine the relative importance of these various factors and mechanisms in the physiological regulation of estrogen biosynthesis in adipose tissue, for example, the increase which occurs as a function of aging, and the variation with regional fat distribution. In particular we will address the concept that breast tumor development is influenced by the regional distribution of estrogen biosynthesis in local areas of the breast, and the mechanisms whereby such gradients of P450arom expression are established and maintained will be investigated. We believe that these studies will provide new insights into the regulation of mammalian gene expression in general as well as of P450arom expression in particular, but especially will throw light on age-dependent processes involving estrogen biosynthesis in adipose tissue, namely the increase that occurs as a function of aging, as well as the implication of adipose tissue estrogen biosynthesis in the development of cancer.
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