Obesity, Aromatase and Breast Cancer Risk.

Approximately two-thirds of adult US women have excess body fat: 36% are obese with a body mass index (BMI) of more than 30, whereas another one-third are overweight (BMI: 25–29).^1,2This degree of obesity is becoming more common all over the world, overweight or obese postmenopausal women have a threefold increased risk for developing breast cancer when compared with normal-weight postmenopausal women.^3-5

Obesity has been associated with abnormally high expression of the enzyme aromatase in the breast, increased local estrogen production, and predisposition to breast hyperplasia and cancer. Increased adiposity in postmenopausal women may trigger signaling pathways that induce aromatase expression. In breast adipose fibroblasts, increased TNF production may induce the distal aromatase promoter, whereas increased local PGE₂ production may induce the proximal promoter region.⁶

In the breast, benign or malignant epithelial cells lie in contact with endothelial cell-lined capillaries, undifferentiated adipose fibroblasts that are also known as preadipocytes, and lipid-filled mature adipocytes.⁷Aromatase, a member of the cytochrome P450 superfamily, is the enzyme responsible for key steps in the synthesis of estrogens.⁸Aromatase is expressed in a several tissues including undifferentiated adipose fibroblasts and breast tumors, but is not expressed in mature adipocytes.^8,9A greatly increased mass of breast adipose tissue in obese women may locally increase estrogen production within the breast simply because of a higher number of aromatase-expressing fibroblasts.⁸In addition to this mass effect, aromatase expression per unit adipose tissue or cell may also increase with weight gain.

Estrogen, a product of the aromatase enzyme in adipose tissue, has long been suspected as the hormone responsible for increasing breast cancer risk in obese postmenopausal women. In fact, the most effective hormonal treatment of postmenopausal breast cancer has been the use of aromatase inhibitors that block aromatase activity in the breast and the periphery, thereby reducing the amount of local estrogen production – which in turn helps to suppress recurrence of the breast tumor tissue^.10A key and unresolved question has been the relative contributions of breast adipose tissue, versus subcutaneous adipose tissue at other body sites, to the formation of estrogen that contributes to increased breast cancer risk and growth. Epidemiologic studies suggested that mildly increased venous blood estrogen levels might account for a portion of the link between obesity and breast cancer incidence.¹¹However, the recently performed randomized Women’s Health Initiative study, demonstrating a possible reduction in breast cancer risk in postmenopausal women that were administered estrogen-only hormone replacement, has challenged the role of mildly elevated circulating estrogen levels in breast cancer risk.^12,13

Over the past two decades it has suggested that breast adipose tissue fibroblasts are a crucial site for aromatase expression and estrogen production, and has linked them to the development of breast cancer.^7,14,15 By the same token, the malignant epithelial cells in an existing breast tumor are in direct contact with the surrounding adipose tissue, which is a major supplier of estrogen to cancer.^16,17It is thus tempting to hypothesize that obesity may be associated with abnormally high expression of aromatase in breast adipose tissue fibroblasts, resulting in elevated levels of local estrogen in the breast and predisposition to breast hyperplasia and cancer. It is plausible that obesity may trigger signaling pathways that induce aromatase expression. In fact, obesity is known to robustly increase adipose tissue levels of tumor necrosis factor (TNF), a known inducer of aromatase expression in adipose fibroblasts.^18,19Obesity may also increase other local hormones such as prostaglandin E₂ (PGE₂) that are also known to induce aromatase gene expression in adipose tissue of the breast and elsewhere.^19,20Aromatase in breast adipose tissue (versus adipose tissue at other body sites) might have a substantially higher impact on carcinogenesis because of its proximity to breast epithelial cells.

In summary, both breast density and obesity are associated with an abnormally high expression of the enzyme aromatase locally in the breast and an increased risk of breast cancer.

1. Flegal KM, et al. Prevalence and trends in obesity among US adults, 1999-2008.JAMA. 2010; 303:235–241.
2. Sutton-Tyrrell K, et al. Reproductive hormones and obesity: 9 years of observation from the Study of Women’s Health Across the Nation. J. Epidemiol. 2010; 171:1203–1213.

Ziegler RG, et al. Relative weight, weight change, height, and breast cancer risk in Asian–American women. J. Natl. Cancer Inst. 1996; 88:650–660.