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. The increased breast cancer risk in obese postmenopausal women has been attributed, 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. Chronic inflammation increases the risk of multiple tumor types. A link between obesity, breast inflammation and HR-positive breast cancer was previously unknown. Obesity causes subclinical inflammation in visceral and subcutaneous white adipose tissue, characterized by macrophages surrounding dead adipocytes forming crown-like structures (CLS). Recently, we found increased numbers of CLS, activation of the NF-κB transcription factor, increased levels of pro-inflammatory mediators including PGE2 and elevated aromatase levels in the mammary glands of obese mice. In vitro models were utilized to demonstrate the importance of COX-2-derived PGE2 for the induction of aromatase. These preclinical findings raised the possibility that the obesity-inflammation-aromatase axis is important for breast carcinogenesis. Importantly, these findings have now been translated to women. Breast tissue was obtained from women who underwent surgery. CLS of the breast (CLS-B) were found in nearly 50% of patient samples. The severity of breast inflammation, defined as the CLS-B index, correlated with both body mass index and adipocyte size. Consistent with our preclinical findings, increased NF-κB binding activity, increased levels of pro-inflammatory mediators and elevated aromatase expression were found in the inflamed breast tissue of overweight and obese women. Notably, levels of COX-2 and PGE2 correlated with levels of aromatase and the progesterone receptor, an estrogen receptor-α regulated gene. The discovery of the connection between obesity, breast inflammation and changes in the expression of genes linked to breast cancer provides a mechanistic rationale for the development of behavioral, dietary and pharmacological strategies to reduce the risk of breast cancer. Recently conducted caloric restriction experiments provide proof-of-principle evidence that obesity-related mammary gland inflammation including related molecular changes can be reversed. Moreover, treatment with celecoxib, a selective COX-2 inhibitor, suppressed both the elevated levels of PGE2 and aromatase activity found in the mammary glands of obese mice. A clinical trial is underway in an attempt to translate these promising preclinical findings.
Citation Format: Andrew J. Dannenberg. Obesity, inflammation and breast cancer. [abstract]. In: Proceedings of the Twelfth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2013 Oct 27-30; National Harbor, MD. Philadelphia (PA): AACR; Can Prev Res 2013;6(11 Suppl): Abstract nr PL05-02.
RSS Feeds