Abstract
Obesity is now considered as a risk factor for breast cancer in postmenopausal women. Adipokine levels are modulated in obesity, and may play a role in carcinogenesis. Moreover, obesity increases risk of cancer mortality. Here, we hypothesized that this increase could be due to a modification in angiogenesis, capital event in the development of metastases, and/or in effectiveness of cancer treatments. To test these assumptions, following a same experimental design and simultaneously the effects of leptin and adiponectin on angiogenesis were investigated, and the impact of hyperleptinemia on anticancer drug effectiveness was measured in physiological and obesity situations. Focusing on angiogenesis, the proliferation of endothelial cells (HUVEC), which expressed leptin and adiponectin receptors, was stimulated by leptin and inhibited by adiponectin. Both adipokines globally reduced apoptosis and caspase activity. Leptin increased migration whereas adiponectin decreased migration, and leptin enhanced the area of the tubes formed by HUVEC cells while adiponectin inhibited their formation. MCF7 and MDA-MB-231 cells treated with leptin secreted more VEGF than untreated cells, whereas adiponectin treatment inhibited VEGF secretion. Finally, MCF7 cells pre-treated with leptin were more invasive than untreated cells. This effect was not reproduced in MDA-MB-231 cells. In the MCF7 breast cancer cell line, leptin could induce cell proliferation and reduced the efficacy of all breast cancer therapies (tamoxifen, 5-fluorouracil, taxol and vinblastin). These results suggest that, in obesity situation, leptin– in contrast to adiponectin – may promote tumor invasion and angiogenesis, leading to metastases ‘apparition, and reduce treatment efficacy, which could explain the increased risk of cancer mortality in cases of overweight. The evidence suggests adipokines influence breast cancer issue and could play a significant role, especially in obese patients for which hyperleptinemia, hypoadiponectinemia and increased metastatic potential are described.
Highlights
Obesity, characterized as an excess of adipose tissue [1], is a global health problem associated with a variety of metabolic diseases such as diabetes and an increased risk of developing cancer, including breast cancer [2], [3]
In complete medium containing vascular endothelial growth factor (VEGF) and bFGF, human leptin had no effect on HUVEC proliferation (Fig. 2A)
When the experiment was realized without VEGF and bFGF, human leptin stimulated HUVEC proliferation in a dose-dependent manner, and a significant increasing effect was observed at concentrations reflecting obesity conditions and pharmacological concentrations at 96 h (+21 and +75% at 100 and 1 000 ng/mL respectively, p,0.05) compared to leptin-free controls (Fig. 2B)
Summary
Obesity, characterized as an excess of adipose tissue [1], is a global health problem associated with a variety of metabolic diseases such as diabetes and an increased risk of developing cancer, including breast cancer [2], [3]. Clinical studies indicate that increased BMI is associated with increased breast cancer recurrence, more aggressive tumors, and a shorter survival period [4,5,6]. Adipose tissue is widely considered as an active endocrine organ, and there is an increasing evidence to suggest adipose tissue may play an important role in breast cancer development by surrounding the mammary gland. The excess of fat increases the synthesis and secretion of bioactive peptides called adipokines, which include leptin and adiponectin [6], [10,11,12,13]
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