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BMC Cancer  2008 

Leptin/HER2 crosstalk in breast cancer: in vitro study and preliminary in vivo analysis

DOI: 10.1186/1471-2407-8-305

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Expression of ObR, HER2, phospo-HER2 was assessed by immonoblotting. Physical interactions between ObR and HER2 were probed by immunoprecipitation and fluorescent immunostaining. Expression of leptin and ObR in breast cancer tissues was detected by immunohistochemistry (IHC). Associations among markers studied by IHC were evaluated using Fisher's exact test for count data.HER2 and ObR were coexpressed in all studied breast cancer cell lines. In MCF-7 cells, HER2 physically interacted with ObR and leptin treatment increased HER2 phosphorylation on Tyr 1248. In 59 breast cancers, the presence of leptin was correlated with ObR (the overall association was about 93%). This result was confirmed both in HER2-positive and in HER2-negative subgroups. The expression of leptin or ObR was numerically more frequent in larger (> 10 mm) tumors.Coexpression of HER2 and the leptin/ObR system might contribute to enhanced HER2 activity and reduced sensitivity to anti-HER2 treatments.Recent epidemiological and clinical data confirmed that obesity in postmenopausal women is associated with increased breast cancer risk, development of more aggressive breast tumors and resistance to certain anti-breast cancer treatments [1-4]. The molecular mechanisms of this link are not clear, but several studies in animal and cellular models suggested that excess body weight could promote breast cancer through increased production of an adipocyte-derived hormone leptin [5-7]. The primary function of leptin is to regulate energy balance and food intake by acting in the brain, but the hormone also plays an important role in peripheral organs, modulating fertility, lactation, and immune response [8,9]. Leptin levels in humans correlate with adiposity and are usually higher in females than in males [8].Leptin action is mediated through the transmembrane leptin receptor ObR [10]. The human ObR can be expressed as at least four isoforms with different COOH-terminal cytoplasmic domains [11]. The full (long)


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