Abstract CN12-02: The prostaglandin-aromatase connection: Implications for breast carcinogenesis
Authors: Dannenberg Andrew J. 
Published: January 2011

Abstract
More than 40,000 women in the U.S. die each year of metastatic breast cancer. Notably, obese postmenopausal women are at increased risk of developing hormone receptor (HR)-positive breast cancer. Approximately two-thirds of breast cancer patients have tumors that express estrogen receptors and require estrogen for tumor growth. Estrogens are synthesized from androgens in a reaction catalyzed by cytochrome P450 aromatase (aromatase), encoded by the CYP19 gene. After menopause, peripheral aromatization in adipose tissue is largely responsible for estrogen production. Thus, the increased breast cancer risk in obese postmenopausal women is believed to be attributable, at least in part, to elevated levels of circulating estrogen related to both increased adipose tissue and elevated aromatase expression. Given the epidemic of overweight and obese subjects in the U.S., there is a pressing need to develop mechanism-based strategies to reduce the cancer risk among this sector of the population. Numerous studies have been performed to elucidate the mechanisms that regulate the transcription of CYP19. Several groups have suggested that prostaglandin E2 (PGE2) is a clinically important inducer of aromatase. PGE2 stimulates cAMP-dependent signaling leading to enhanced CYP19 transcription. Cyclooxygenases (COX) catalyze the first step in the synthesis of PGE2 from arachidonic acid. Positive correlations have been detected between COX and aromatase expression in human breast cancer specimens. In mice which express a mammary-targeted COX-2 transgene, increased PGE2 and aromatase levels were observed. Silencing of 15-hydroxyprostaglandin dehydrogenase, the key enzyme responsible for inactivating PGE2, upregulated aromatase. Recently, the tumor suppressor, BRCA1, was found to negatively regulate CYP19 expression. This inhibitory effect of BRCA1 on aromatase expression was relieved by PGE2. Finally, two observational studies found that use of aspirin, an inhibitor of PGE2 production, was associated with a reduced risk of hormone receptor-positive breast cancer. Collectively, these findings provide a strong rationale for targeting the PGE2-aromatase axis as a risk reduction strategy. In both dietary and genetic models of obesity, evidence will be presented that obesity causes significant inflammation in the mammary gland and visceral fat. Elevated levels of proinflammatory mediators (TNF-alpha, IL1-Beta and COX-2) were found in these inflamed tissues. Levels of aromatase mRNA and activity were also increased in both the mammary gland and visceral fat of obese mice and paralleled the increased levels of proinflammatory mediators. Complementary in vitro studies suggested that the observed increase in aromatase reflects, in part, a paracrine mechanism involving both activated macrophages and adipocytes. Silencing or inhibiting COX-2 attenuated the induction of aromatase. Collectively, these findings strongly suggest the possibility that obesity-related inflammation in both the mammary gland and visceral fat contributes to elevated aromatase activity and thereby an increased risk of HR-positive breast cancer. Importantly, our findings provide the basis for future studies to determine whether pharmacological and/or dietary strategies can be used to disrupt the obesity-inflammation-aromatase axis to reduce the risk of HR-positive breast cancer in obese postmenopausal women.
Citation Information: Cancer Prev Res 2010;3(12 Suppl):CN12-02.