Leptin has received considerable interest with respect to obesity. Released into the blood from fat cells, leptin binds to CNS receptors inhibiting food intake, reducing body weight and stimulating energy expenditure. Despite the promise that leptin agonists may have for the treatment of both diabetes and obesity, such molecules have only met with limited success in clinical trials. This lack of effect has been suggested to result from the development of leptin resistance. It will be difficult to harness the therapeutic potential of leptin until this issue of resistance has been overcome. In the meantime molecules such as Axokine (ciliary neurotrophic factor; CNTF) which act via the same intracellular signaling pathway as leptin hold greater promise for the treatment of obesity .

Italian researchers have recently identified a further potential hurdle to the development of leptin as a therapeutic target since it provides a link between excess fat mass and an increased breast cancer risk, particularly in postmenopausal women. This phenomenon is related to the ability of leptin to stimulate estrogen production via an increase in aromatase expression and activity in human adipose stromal cells. This suggest that estrogen biosynthesis occurs through a paracrine mechanism. In addition however, aromatase is also highly expressed in epithelial cancer cells suggesting additional autocrine mechanisms. Although leptin is mainly synthesized by breast adipose tissue, its expression has also been detected in normal and tumoral human mammary epithelial cells. Moreover, leptin receptors are also expressed in normal mammary epithelial cells and in human breast cancer cell lines further supporting leptin stimulation of aromatase activity via an autocrine loop.

Most recently, Sebastiano Andò and colleagues from the University of Calabria have examined this autocrine loop. This group found that leptin induces a three-fold increase in proliferation of the human breast cancer cell line MCF-7 and also an increase in aromatase activity. Increased activity was related to an induction of the aromatase gene, which was in turn related to leptin activation of the human aromatase promoters II and 1.3 (P450arom PII and 1.3). Further analysis led to the conclusion that the effects of leptin were mediated by MAPK or STAT dependent interactions with the AP-1 response element

This study is important since it identifies a potential risk relating to the development of leptin agonists for the treatment of obesity. Perhaps more important however, these data also establish a mechanism for the link between obesity and breast cancer and suggest that molecules that are able to act systemically to block the molecular actions of leptin may confer anti-cancer activity. Breast cancer represents the 4th most common cause of cancer related death in the US having claimed the lives of well over 1 million women between 1970 and 1994. High levels of mortality result from a combination of high incidence and the lack of options open to those patients who fail first line therapy and develop metastases. Additional treatment directions for breast cancer patients are therefore highly sought after. We have recently featured histone deacetylase inhibitors (click here) and retinoids (click here) as therapeutic opportunities. Perhaps leptin blockers should now be included as a further therapeutic target.
 

For a full list of publications relating to Cpd 5 please click here.

Adapted from Catalano et al et al, J Biol Chem 2003 May 6; [epub ahead of print]

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