Adipokine leptin in obesity-related pathology of breast cancer

Abstract

Breast cancer is one of the most common cancers and a leading cause of cancer death in women worldwide. Incidences of breast cancer are substantially higher among postmenopausal than premenopausal women. Obesity is a common risk factor for postmenopausal breast cancer. For the development of postmenopausal breast cancer, several phenomena may function in relation with obesity. It is well known that adipose tissue is the major source of oestrogens in postmenopausal women, and oestrogens are associated with the pathological process of breast cancer. The enzyme aromatase (CYP19), present in the adipose tissue, catalyses the conversion of oestrone from androstenedione, which is mainly produced in the adrenal gland under the influence of adrenocorticotropic hormone. As the rate of oestrogen production is related to the amount of the adipose tissue, the quantity of body fat could be a significant source of oestrogens. Furthermore, there is an inverse association between obesity and circulating levels of sex hormone-binding globulin (SHBG), the principal carrier protein for oestrogen. Lower levels of SHBG increase the free or unbound form of oestrogen in blood, and unbound oestrogens may elevate the risk of breast cancer. Interestingly, a conflicting relationship exists between obesity and breast cancer prognosis. It has been documented that obesity is involved with the pathogenesis of oestrogen receptor-positive (ER+) breast cancer, which usually has a better prognosis than ER− breast cancer. On the other hand, obese women with breast cancer have been found to have a poor prognosis. Consequently some important factors other than the oestrogens may be crucial in the mechanisms by which obesity influences the prognosis of breast cancer. Evidence about the importance of insulin, insulin-like growth factors (IGFs) and leptin is accumulating in this complicated pathological phenomenon (Stephenson and Rose 2003; McTiernan 2005; Goodwin et al. 2012). Systemic low-grade inflammation and insulin resistance are two related mechanisms that have been hypothesized to play a role in the obesity–disease associations. In insulin resistance, serum levels of insulin and IGFs are elevated and the insulin/IGF-I signalling is altered (Probst-Hensch 2010). Furthermore, adipose tissue can act like an endocrine organ, releasing several hormone-like cytokines (adipokines) such as leptin, resistin and adiponectin. The majority of these adipokines, including leptin, participates in the pro-inflammatory processes in obesity and perpetuates the state of insulin resistance. A recent report on breast cancer observed higher expression of leptin and its receptors (Ob-R) at the lesion site in patients with insulin resistance (Carroll et al. 2011). On the other hand, adiponectin is an antiinflammatory adipokine, and a growing body of evidence suggests its anti-cancer effects (Grossmann et al. 2008a; Cleary et al. 2010) (table 1). This review briefly discusses relevant current findings on leptin biology and breast cancer as well as approaches to modulate the deleterious effects of this adipokine.