Análisis Histórico

Leptin is a hormone produced mainly by adipocytes that is involved in regulating body weight (334). After production in adipose tissue, leptin circulates in plasma eventually reaching the central nervous system, where it binds to the leptin receptor and upregulates anorexigenic peptides and downregulates orexigenic peptides (331). As a result, leptin reduces lipid levels and improves insulin sensitivity (331). In mice, leptin deficiency causes

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insulin resistance, obesity, and diabetes, and leptin treatment reverses these conditions (331, 334). Leptin treatment also reverses insulin resistance and diabetes that is due to

lipodystrophy (331, 334). In non-obese humans, leptin is associated with decreased appetite and increased energy metabolism. Leptin levels are higher in the obese, suggesting that these individuals are no longer sensitive to leptin signaling, but the exact mechanism for this ‘leptin resistance’ has not been described (331).

Leptin is expressed in a variety of tissues, including adipose tissue, normal breast, breast cancer cell lines, and human breast tumors (377, 378). Ishikawa et al. (378) noted that there may be differences in patterns of leptin expression between malignant and benign tissues – normal breast displayed weak leptin staining whereas malignant breast cells

typically displayed strong staining, similar to the levels seen in adjacent adipocytes. Caldefie- Chezet et al. (379) did not observe leptin expression in normal tissue from healthy breasts, but did observe leptin expression in phenotypically normal glands adjacent to tumor in affected breasts. Leptin receptor isoforms are present in human breast tumors and breast cancer cell lines (319, 320, 322, 378), but were not observed in normal human breast tissue (378).

There is growing evidence that leptin may play a role in the development of normal and cancerous breast tissue. Normal mammary growth (ductal branching and development) is impaired in leptin-deficient and leptin receptor–deficient mice (322, 380). Work by Cleary et al. (380) showed that transgenic TGF-α/LEPob LEPob genetically obese mice did not

experience spontaneous mammary tumors, compared to 58 tumors in transgenic TGF-α/LEP+ LEP+ homozygotes and 63 tumors in TGF-α/LEPob LEP+ heterozygotes during the same 2 year observation period. Similar results were obtained for TGF-α/LEPRdb LEPRdb genetically

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obese mice, indicating that deficiencies in the leptin ligand-receptor unit inhibit normal and neoplastic mammary growth (380).

In vitro, leptin stimulates proliferation of normal and cancerous cells. In MCF-7 and

T47D breast cancer cell lines, leptin stimulates STAT3 and MAP kinase signaling (319, 320). Leptin also increases cell proliferation and DNA synthesis in MCF-7, T47D, and HBL100 cell lines (319-322), and increases anchorage-independent growth in malignant (T47D) but not normal (HBL100) breast cell lines (322). In Catalano et al. (259), leptin enhanced aromatase expression and activity in MCF-7 cells, suggesting that the effect of leptin expression on cell proliferation may be mediated by estrogen receptor signaling.

Reports of associations between serum leptin and breast cancer do not reveal a consistent trend. Studies in Chinese and Taiwanese populations reported that leptin was higher in breast cancer cases compared to controls (381, 382), but in Petridou et al. (383) leptin levels were significantly lower in premenopausal cases compared to controls and there was no difference among postmenopausal subjects. Mantzoros et al. (384) reported no association between mean leptin levels and DCIS in premenopausal women. Some of the inconsistency in the studies mentioned above may be due to the measurement of leptin after breast cancer diagnosis in cases. A Swedish nested case-control study measured leptin levels prospectively and found no association between leptin levels and breast cancer (385).

Several studies indicate that polymorphisms in the leptin and leptin receptor genes may have an effect on serum leptin levels, leptin receptor levels, and breast cancer risk. Snoussi et al. (386) reported that the leptin -2548 G/A polymorphism was associated with breast cancer in a dose-dependent manner, but in Cleveland et al. (387) only the AA

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that the LEP -2548 polymorphism was associated with plasma leptin receptor levels and leptin/leptin receptor ratios in women, but not in men. In vitro functional assays of this SNP have not been reported so it is unclear whether these associations are directly related to the - 2548 G/A SNP or other genetic polymorphisms in linkage disequilibrium with the -2548 locus.

Leptin receptor polymorphism codon 109 RR variant homozygotes had higher serum leptin levels compared to codon 109 KR heterozygotes in healthy Korean controls, but the K109R polymorphism was not associated with breast cancer (389). In van Rossum et al. (390), the 109R variant was associated with higher leptin levels among subjects who had gained weight over the course of the study, but there was no difference in leptin levels by genotype among subjects with stable weight. Some studies have reported that the LEPR codon 223R variant is associated with higher serum leptin levels postmenopausal women (391), and with breast cancer (382, 386). The LEPR codon Q223R polymorphism was not associated with breast cancer in two other studies (387, 389). Woo et al. (389) also reported no association between breast cancer and LEPR SNPs K656N and P1019P.

Some LEPR polymorphisms are also associated with obesity. Clement et al. (392) described a rare LEPR mutation (exon 16 G → A) that leads to early onset morbid obesity in homozygotes. In other studies, the LEPR amino acid change Q223R was associated with obesity among Greek men and women and British women (391, 393), but K109R and K656N were not (393). LEPR polymorphisms at codons K109R, K204R, Q223R, and K656N were not associated with obesity in Danish men (394).