Table 4.

Possible mechanisms relating recently proposed biomarkers to postmenopausal breast cancer risk and physical activity

Proposed BiomarkerPossible role in postmenopausal breast cancerPossible impact of physical activity in postmenopausal women
LeptinInduces aromatase and stabilizes estrogen receptor-α (57, 122, 124, 266-268).Weight loss decreases body fat, which is the main source of circulating leptin (122-124).
Although leptin can improve insulin sensitivity (145), elevated leptin levels are associated with insulin resistance (117). Hypothalamic actions of leptin could theoretically decrease systemic insulin sensitivity and adiponectin production (269).
Expression is induced by high levels of estrogens and insulin (124, 141, 268).
Mitogen in breast cancer cells (15); inhibits apoptosis; pro-angiogenic (111, 122, 124, 141).
AdiponectinGene expression and secretion from adipocytes are reduced by TNF-α and IL-6 (57, 142); production might also be reduced partially by leptin (269).Fat loss decreases IL-6 and TNF-α (138), which are potent inhibitors of adiponectin expression and secretion (139). Hence, weight loss may increase circulating adiponectin levels. Chronic physical activity may lower inflammation (e.g., circulating IL-6, TNF-α) independently of fat loss (118); however, the mechanisms for this effect are unknown.
Promotes and enhances insulin sensitivity (140, 142, 144, 270); reduced adiponectin leads to insulin resistance and compensatory hyperinsulinemia (271).
Antiangiogenic (272); antimitogenic, and anti-inflammatory (111). In one breast cancer cell line adiponectin had no effect on apoptosis but did inhibit cell proliferation (273).
TNF-αA key regulator of IL-6 synthesis (57).Fat loss may decrease TNF-α levels given that TNF-α mRNA and TNF-α protein are released from adipose tissue in obesity (153-155).
Stimulates estrogen biosynthesis via aromatase induction (166).Chronic physical activity may reduce the number of mononuclear cells in the blood thereby depleting a source of TNF-α (138).
Induces insulin resistance (109, 164).
Paradoxical action: inhibits tumor cell proliferation (274) but also acts as a tumor promoter (151, 152, 275). Can cause direct DNA damage; antiapoptotic and mitogenic (151); promotes invasion, angiogenesis and metastasis of tumor cells (114, 150, 152).
IL-6Release is stimulated by TNF-α; has been speculated that systemic IL-6 reflects ongoing production of TNF-α (164, 165); IL-6 in turn, exerts inhibitory effects on TNF-α (165).Although the acute effects of exercise on IL-6 levels have been studied widely (160), the mechanisms whereby chronic physical activity alter IL-6 levels are unclear (161).
Plays a primary role in stimulating hepatic production of CRP (159).Reduced adiposity may decrease IL-6 levels given that IL-6 originates from adipose tissue (162), among other sources.
Produces insulin resistance in adipocytes (276, 277); possible role in type 2 diabetes (160).Chronic physical activity may reduce the number of mononuclear cells in the blood thereby depleting a source of IL-6 (138).
Stimulates estrogen biosynthesis by the induction of aromatase activity (166).
Promotes breast cancer cell motility suggesting a role in metastasis (167).
Complex role of IL-6 in breast cancer cells in vitro. Up-regulates antiapoptotic and angiogenic proteins in tumor cells but also induces apoptosis in estrogen receptor–positive mammary carcinoma cell lines (172).
CRPA prototypical marker of inflammation (174).Long-term physical activity may decrease CRP by reducing adiposity, by reducing cytokine production (i.e., IL-6 and TNF-α) in muscle and mononuclear cells, or by other means (179).
Production is promoted by TNF-α and IL-6 (112).
Independently associated with leptin in healthy individuals, possibly via induction of IL-6 by leptin (278).
CRP production is strongly, positively related to insulin resistance and can change with insulin levels independently of changes in obesity (279).