MS, according to the National Cholesterol Program (NCEP) Adult Treatment Panel III (ATP III), can be defined as the presence of at least three of the following clinical criteria: waist circumference

>88 cm in women, HDL-C <50 mg/dl, blood pressure ≥130/85 mmHg, triglyceride >150 mg/dl and insulin resistance [3]. The prevalence of MS is high in the general population with approximately 34% of adults meeting the above-mentioned criteria and increases with age and body mass index (BMI). In fact, women over 60 years and overweight SB525334 or obese are much more likely to meet the MS criteria [4]. Consistently, post-menopausal women are often affected by MS and, interestingly, show the highest incidence of breast cancer in the female population [1]. Although many epidemiological studies link obesity and MS to the increased frequency of many cancer types, the molecular mechanisms underlying this increased risk are still poorly characterized. Visceral adipose tissue has multiple endocrine, metabolic and immunological functions and has been

shown to be central in the MS pathogenesis. MS is a pro-inflammatory, pro-coagulant state associated with insulin resistance [5, 6]. The increase in adipose tissue mass, which characterizes MS, can have both direct and secondary effects favouring tumorigenesis [6]. Obese patients often develop insulin resistance with various tissues showing low cell sensitivity to insulin activity. As a consequence, NVP-HSP990 a balancing mechanism stimulates insulin release resulting in a chronic compensatory hyperinsulinemia. By continuously stimulating insulin signalling in sensitive tissues, high levels of circulating insulin cause aberrantly increased mitogenic and antiapoptotic effects [7]. Although the obese state generates peripheral insulin resistance in many tissues, not all insulin signalling is impaired. In the diabetic liver, the gluconeogenic pathway becomes insulin resistant, and insulin-stimulated lipogenesis remains sensitive. Thus, in insulin-resistant patients, specific

tissues and signalling pathways Idoxuridine can remain insulin-sensitive and are exposed to higher than normal levels of insulin signalling. Initial experiments demonstrated that in human breast cancer cell lines insulin has been shown to promote DNA synthesis, suggesting a mitogenic effect [6]. When insulin concentrations are high, insulin — which is structurally similar to insulin-like growth factor 1 and 2 (IGF1 and IGF2) — acts also as a growth factor by binding the IGF-receptors (IGF1R and IGF2R) [8, 9]. Moreover, increased insulin signalling can induce overexpression of the receptors [9]. Consistently, in vitro and in vivo studies have shown insulin receptor overexpression in breast tissue.