The long-range goal is to define the epithelial-stromal interactions responsible for aromatase expression and estrogen production in breast cancer tissue. The overall hypothesis is that upregulated aromatase expression in breast fibroblasts increases the tissue concentration of estradiol (E2), which enhances development and growth of malignant breast epithelial cells. This clinically pertains, since aromatase inhibitors (Als) are the most effective hormonal treatment of breast tumors. A single gene encodes aromatase, the key enzyme in estrogen biosynthesis, the inhibition of which by an Al effectively eliminates E2 production. We showed that 81% of estrogen production in breast cancer tissue was accounted for by the aberrant activation of the alternatively used promoter I.3/II region, which is coordinately regulated by PGE2 and its downstream signaling effectors/transcription factors p38/ATF-2, JNK/c-jun and BRCA1 in breast adipose fibroblasts. Selective inhibition of this promoter region may treat beast cancer while permitting aromatase expression at other body sites and thus obviate the key side effects of the current Als. The mechanisms that regulate the promoter I3/II region will be investigated under the following aims:1A. To identify p38 and JNK-dependent transcriptional regulators that stimulate aromatase expression in breast adipose fibroblasts. PGE2 secreted by malignant cells upregulates the aromatase promoters I.3/II significantly both in vivo in breast tumor tissue and in vitro in cultured breast adipose fibroblasts. We will test the hypothesis that the transcription factors ATF-2 and c-jun activated by p38 and JNK are necessary for PGE2-dependent transcriptional activation of aromatase via the promoter I.3/II region in breast adipose fibroblasts. 1B. To determine in vivo phosphorylation of p38, ATF-2, JNK and c-jun in fibroblasts in breast tumors. 2A. To define the role of BRCA1 in the regulation of aromatase expression in breast adipose fibroblasts. We will test the hypothesis that BRCA1 interacts with the transcriptional complex at promoters I.3/II to inhibit their transactivation, whereas reduced BRCA1 levels fail to repress aromatase expression. 2B. To determine in vivo differential expression of aromatase and other key PGE2/estradiol-related genes in BRCA1 haplo insufficient breast tissues from mutation carriers vs. noncarrier controls. Proposed studies may lead to new pilot trials of treatment and prevention using p38/JNK inhibitors in BRCA1 mutation carriers. ? ? ?
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