Obesity, inflammation, and postmenopausal breast cancer: therapeutic implications

Abstract

Breast cancer is the female malignant neoplasia with the highest incidence in the industrialized world. Although early diagnosis has contributed to therapeutic success, breast cancer remains a major health issue. In the last few year the hormone therapy for estrogen-dependent breast cancer has evolved achieving significant clinical results; at the same time, it has enabled us to better define the role of estrogens in the etiopathogenesis of this tumour. Weight increase and obesity have been identified as the most important risk and prognostic factors for breast cancer in postmenopausal women. Several hypotheses have been proposed to explain the association of obesity with postmenopausal breast cancer. Specific obesity-associated factors, including leptin, insulin and inflammatory mediators, seem to influence breast cancer growth and prognosis independently of estrogens and at least in part by interacting with estrogen signalling at a cellular level. Therefore, a careful assessment of the nutritional status and body composition is paramount for a proper therapeutic approach for postmenopausal breast carcinoma. The use of antidiabetic and anti-inflammatory drugs associated with conventional hormone therapies and dietary/physical interventions could offer a new therapeutic approach for breast carcinoma that develops in the context of adiposity.

Keywords: Obesity; aromatase inhibitors; breast cancer; inflammation; metformin; oxidative stress; postmenopausal women.

Figure 1

Different mechanisms of estrogen dependence for hormone-related breast cancer in pre- and postmenopausal women. In premenopausal women, the main site of synthesis of estrogen is the ovary. In postmenopausal women, adipose tissue is the main source of the circulating estrogens. Adipose tissue produces the enzymes aromatase; therefore, in obese women, there is an increased conversion of the androgens androstenedione and testosterone into the estrogens: oestrone and oestradiol, respectively, by aromatase. Moreover, obesity, being associated with metabolic syndrome, results in increasingly circulating levels of insulin and insulin-like growth factor, which, by acting as mitogens for epithelial breast cells, stimulate their neoplastic degeneration. Moreover, adipocytes produce several “adipokines” such as leptin and inflammatory cytokines which can influence aromatase activity and estrogen-dependent cell proliferation. IGF, insulin growth factor; IL, interleukin; TNF-α, tumour necrosis factor-α; Lp, leptin; E, estradiol; A, aromatase.

Figure 2

Potential therapeutic approaches for postmenopausal hormone-dependent breast carcinoma which develops in the context of adiposity. Adipokines-, insulin-, inflammation-, and angiogenesis-signalling pathways influence the development of hormone-dependent breast carcinoma and might represent new targets of treatment in combination with conventional hormone therapies. COX-2, cyclooxygenase-2; E, estradiol; HGF, hepatocyte growth factor; IGF, insulin growth factor; IL, interleukin; TNF, tumour necrosis factor; VEGF, vascular endothelial growth factor.