Abstract
Obese postmenopausal women have an increased breast cancer risk, the principal mechanism for which is elevated estrogen production by adipose tissue; also, regardless of menstrual status and tumor estrogen dependence, obesity is associated with biologically aggressive breast cancers. Type 2 diabetes has a complex relationship with breast cancer risk and outcome; coexisting obesity may be a major factor, but insulin itself induces adipose aromatase activity and estrogen production and also directly stimulates breast cancer cell growth and invasion. Adipose tissue inflammation occurs frequently in obesity and type 2 diabetes, and proinflammatory cytokines and prostaglandin E2 produced by cyclooxygenase-2 in the associated infiltrating macrophages also induce elevated aromatase expression. In animal models, the same proinflammatory mediators, and the chemokine monocyte chemoattractant protein-1, also stimulate tumor cell proliferation and invasion directly and promote tumor-related angiogenesis. We postulate that chronic adipose tissue inflammation, rather than body mass index-defined obesity per se, is associated with an increased risk of type 2 diabetes and postmenopausal estrogen-dependent breast cancer. Also, notably before the menopause, obesity and type 2 diabetes, or perhaps the associated inflammation, promote estrogen-independent, notably triple-negative, breast cancer development, invasion and metastasis by mechanisms that may involve macrophage-secreted cytokines, adipokines and insulin.
Highlights
Carcinoma of the breast continues to be the most commonly occurring cancer, with the exception of non-melanomatous skin cancers, in American women, it is second to lung cancer as the most common cause of cancer-related deaths [1]
The prominence of central obesity in type 2 diabetes, its association with hyperinsulinemia in non-diabetic women, and its function as a risk factor for postmenopausal breast cancer and negative influence on prognosis, all raise the question of the extent to which the perceived role of hyperinsulinemia is due to the accompanying obesity-related elevation in extraglandular estrogen production that occurs after the menopause
Future research should focus on the relationships between metabolically compromised obesity and adipose tissue inflammation to determine the level of breast cancer risk beyond the limits set by a body mass index (BMI)-based definition of adiposity
Summary
Carcinoma of the breast continues to be the most commonly occurring cancer, with the exception of non-melanomatous skin cancers, in American women, it is second to lung cancer as the most common cause of cancer-related deaths [1]. An analysis by Wildman et al [50] of data from 1889 postmenopausal American women who participated in the Women’s Health Initiative Observational Study found that 45.1% of all those of normal weight (BMI < 25 kg/m2) had an increased risk of type 2 diabetes and cardiovascular disease as judged by the presence of cardiometabolic abnormalities (“metabolically obese-normal weight”), compared with 72.3% of all overweight or obese women (BMI ď 25 kg/m2) These women had plasma biomarkers of adipose tissue inflammation, including elevated CRP and, to a lesser degree, TNF-α and IL-6 concentrations
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