Adipokines (leptin, adiponectin, and hepatocyte growth factor (HGF)) secreted from adipose tissue have come to be recognized for their contribution to the mechanisms by which obesity and related metabolic disorders influence breast cancer risk. In this review, we discuss the direct and indirect effects of these protein factors on the biological and clinical aspects of breast cancer biology, and emphasize their distinctive modes of action through endocrine-, paracrine-, and autocrine-mediated pathways. The stimulatory effects of leptin on breast cancer growth were considered to occur primarily via activation of the estrogen receptor; however, new evidence suggests that leptin may be acting on downstream cell signaling pathways in both estrogen-dependent and -independent cell types. Another secretory adipokine, HGF, may act largely not only to promote tumor cell invasion, but also to enhance tumor growth indirectly by stimulating angiogenesis. In contrast, adiponectin, an endogenous insulin sensitizer, exerts a direct growth-inhibitory effect on tumor cells by downregulating cell proliferation and upregulating apoptosis, and also inhibits tumor-related angiogenesis.

Objective: Socioeconomic deprivation is associated with an increased risk of breast cancer mortality. This article summarizes the relationships between socioeconomic status (SES) and breast cancer in white European women compared with racial and ethnic groups in the United States. Furthermore, we examine the association between obesity and breast cancer within socioeconomic disparities. Methods: Mortality rates were published by the American Cancer Society and the National Cancer Institute Surveillance, Epidemiology, and End Results Program. Obesity data were derived from the National Center for Health Statistics Behavioral Risk Factor Surveillance System. MEDLINE searches were performed using keywords, such as socioeconomic status, poverty, African American, Hispanic, race, and combined with related articles. Results: Socioeconomic deprivation may be responsible for the increased risk of breast cancer mortality in African American and Hispanic patients, as they are more likely than white American patients to be diagnosed with advanced disease. Among white women, social deprivation is related to poor breast cancer prognosis, with increased prevalence rates of high-grade, estrogen receptor (ER)-negative tumors, similar to that of triple-negative breast cancers observed in African American and Hispanic women. Obesity is associated with advanced breast cancer at diagnosis, high tumor proliferation rates, and more triple-negative phenotypes, indicating that it may adversely contribute to prognosis. Conclusions: Most studies show an effect of SES on breast cancer incidence and prognosis. Research should focus on the influence of social deprivation on breast cancer characteristics, such as absence of ER expression, that occurs in African Americans and Hispanics and in white European women with a different genetic background.

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.

Background: Our objective was to determine the clinicopathologic features of triple-negative (estrogen receptor, progesterone receptor, and human epidermal growth factor-2 receptor negative) breast cancer and their relationship to obesity in women drawn from a population with one of the highest obesity rates in the United States. Methods: This retrospective study involved 620 White patients with invasive breast cancer in West Virginia. Hospital tumor registry, charts, and pathology records provided age at diagnosis, tumor histologic type, size, nodal status, and receptor status. Body mass index was calculated and a value of ≥30 was considered indicative of obesity. Results: Triple-negative tumors occurred in 117 (18.9%) of the 620 patients, most often in association with invasive ductal carcinomas. Patients with triple-negative tumors were younger than those with other receptor types, 44.5% and 26.7%, respectively, being diagnosed at age <50 years (P = 0.0004). The triple-negative tumors were larger (P = 0.0003), most notably in the younger women, but small tumors (<2.0 cm) were more often accompanied by lymph node metastases. Obesity was present in 49.6% of those with triple-negative tumors but in only 35.8% of those with non-triple-negative tumors (P = 0.0098). Lymph node metastases were more frequently associated with T₂ tumors in obese patients (P = 0.032) regardless of their receptor status. Conclusions: Triple-negative breast cancers within a White, socioeconomically deprived, population occurred in younger women, with later stage at diagnosis, and in association with obesity, which itself has been associated with a poor prognosis in breast cancer. (Cancer Epidemiol Biomarkers Prev 2008;17(12):3319–24)