Andrew J. Dannenberg, from Cornell University New York, NY discussed some of the factors linking obesity, chronic inflammation and breast cancer at the recent 2011 AACR meeting, Orlando, USA.

Obesity is a risk factor for the development of breast cancer in postmenopausal women and has been associated with an increased risk of breast cancer recurrence and reduced survival.

Obese postmenopausal women are at increased risk of developing hormone receptor (HR)-positive breast cancer. Approximately two-thirds of breast cancer patients have tumours that express oestrogen receptors and require oestrogen for tumour growth. Oestrogens are synthesized from androgens in a reaction catalyzed by enzymes called ‘aromatases’. Aromatase inhibitors are frequently used to treat cancers in which oestrogens are thought to be stimulating their growth.

After menopause, peripheral aromatization in adipose tissue is largely responsible for oestrogen production. Thus the increased levels of circulating oestrogen due to both increased adipose tissue and elevated aromatase expression is thought to be a factor in increasing breast cancer risk in obese postmenopausal women. Numerous studies have been performed to elucidate the mechanisms that regulate aromatization. Prostaglandin E2 (PGE2) is a clinically important inducer of aromatase and PGE2 synthesis is regulated by Cyclooxygenases (COX). In fact in some human breast cancer specimens high levels of COX correlate with high aromatase expression.

Recently, the tumour suppressor, BRCA1, was found to inhibit, aromatase expression but this was relieved by PGE2. Various studies have now reported that the 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.

Dannenberg then went on to discuss the link between obesity and chronic inflammation in increasing the risk of several epithelial malignancies including breast cancer. His studies were carried out in diet induced obese mice.

He found that in these animal models obesity causes significant inflammation in the mammary gland and visceral fat. Elevated levels of pro-inflammatory mediators (TNF-alpha, IL1-Beta and COX-2) were found in the mammary tissues of obese mice. Aromatase levels were also increased in both the mammary gland and visceral fat of these mice and paralleled the increased levels of proinflammatory mediators. By inhibiting COX-2 in these studies aromatase levels were reduced. 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. These 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.