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

Fiorio, Elena; Mercanti, Anna; Terrasi, Marianna; Micciolo, Rocco; Remo, Andrea; Amato, Alessandra; Molino, Annamaria; Parolin, Veronica; Stefano, Bruno Di; Bonetti, Marco; Giordano, Antonio; Cetto, Gian Luigi; Surmacz, Eva

doi:10.1186/1471-2407-8-305

Cited by 105 publications

(88 citation statements)

References 47 publications

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“…Our analyses were also corroborated by ex vivo analyses of human breast cancers (Fiorio et al 2008, Grossmann et al 2008, Wu et al 2009). Our results might be relevant for understanding the relationship between obesity and increased risk of breast cancer in obesity, and could envisage a therapeutic setting aimed at targeting LepR during tumor growth.…”

Section: Introductionsupporting

confidence: 69%

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Cellular and molecular crosstalk between leptin receptor and estrogen receptor-α in breast cancer: molecular basis for a novel therapeutic setting

Fusco¹,

Galgani²,

Procaccini³

et al. 2010

Endocrine-Related Cancer

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Obesity is associated with an increased risk of breast cancer. A number of adipocytokines are increased in obesity causing low-level chronic inflammation associated with an increased risk of tumors. The adipocytokine leptin shows profound anti-obesity and pro-inflammatory activities. We have hypothesized that in common obesity, high circulating leptin levels might contribute to an increased risk of breast cancer by affecting mammary cell proliferation and survival. Leptin exerts its activity not only through leptin receptor (LepR), but also through crosstalk with other signaling systems implicated in tumorigenesis. In this study, we focused our attention on the relationship between the leptin/LepR axis and the estrogen receptor-a (ERa). To this aim, we utilized two human breast cancer cell lines, one ERa-positive cell line (MCF 7) and the other ERa-negative cell line (MDA-MB 231). We observed that the two cell lines had a different sensitivity to recombinant leptin (rleptin): on MCF 7 cells, rleptin induced a strong phosphorylation of the signal transducer and activator of transcription (STAT) 3 and of the extracellular related kinase 1/2 pathways with an increased cell viability and proliferation associated with an increased expression of ERa receptor. This response was not present in the MDA-MB 231 cells. The effects induced by leptin were lost when LepR was neutralized using either a monoclonal inhibitory antibody to LepR or LepR genesilencing siRNA. These data suggest that there is a bidirectional communication between LepR and ERa, and that neutralization and/or inactivation of LepR inhibits proliferation and viability of human breast cancer cell lines. This evidence was confirmed by ex vivo studies, in which we analyzed 33 patients with breast cancer at different stages of disease, and observed that there was a statistically significant correlation between the expression of LepR and ERa. In conclusion, this study suggests a crosstalk between LepR and ERa, and could envisage novel therapeutic settings aimed at targeting the LepR in breast cancers.

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Section: Introductionsupporting

confidence: 69%

“…For MCF 7 and MDA-MB 231 infection, 4!10 5 cells were infected with the lentiviral particles (2.5!10 7 TU/ml) for 24 h in the presence of polybrene (3 mg/ml) (Fiorio et al 2008). After this period, the cells were used for the assays as described above.…”

Section: Lentiviral Infectionmentioning

confidence: 99%

Cellular and molecular crosstalk between leptin receptor and estrogen receptor-α in breast cancer: molecular basis for a novel therapeutic setting

Fusco¹,

Galgani²,

Procaccini³

et al. 2010

Endocrine-Related Cancer

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“…In addition, evidence suggests that leptin may be involved in tumorigenesis, particularly in the development of breast, colorectal and prostate cancer (8). Breast cancer patients exhibited significantly higher leptin levels compared with the corresponding controls (18) and the expression of leptin and leptin receptors is more frequent in larger tumors (19). However, the precise correlation between leptin and breast cancer is not well understood.…”

Section: Introductionmentioning

confidence: 96%

Leptin promotes the proliferation and migration of human breast cancer through the extracellular-signal regulated kinase pathway

Sun

2013

Molecular Medicine Reports

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Abstract. Obesity has been associated with an increased risk of postmenopausal breast cancer, which may be due to the expression of leptin. The aim of this study was to determine the role of leptin in the growth of breast cancer cells in nude mice, the proliferation and migration of MCF-7 human breast cancer cells and its downstream signaling pathway. The xenograft mouse model was elicited by injecting MCF-7 human breast cancer cells into the left back axilla and the tumor size was measured every other day. Leptin injected subcutaneously around the tumor site led to an increase in the size and weight of the tumor, whereas the leptin antagonist (LA) significantly inhibited the size and weight of the tumor. Leptin promoted the proliferation and migration of MCF-7 cells and LA inhibited it. The effects of leptin on increasing the size and weight of the tumor in the nude mice and the proliferation and migration of MCF-7 human breast cancer cells were eradicated by pretreatment with LA, the extracellular-signal regulated kinase (ERK) inhibitor PD98059. In the xenograft mouse model the leptin level was increased and leptin increased the phosphorylation of ERK in the MCF-7 cells, whereas LA significantly reduced the phosphorylation of ERK. These results indicated that leptin promotes the growth of breast cancer in the nude mice and increases the proliferation and migration of MCF-7 human breast cancer cells via the ERK pathway.

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“…Altered NRG1/ErbB signalling has been demonstrated during the development and progression of many tumours [2]. Complex crosstalk between ErbB2 receptors and leptin appears to take place in cancer [3], and ErbB2 induces leptin transcriptional upregulation in human breast epithelial cells [4]. As leptin plays a major role in energy balance regulation, and given the link between leptin and NRG1/ErbB signalling in cancer, it was hypothesized that NRG1 treatment might alter leptin levels.…”

Section: Introductionmentioning

confidence: 99%

Neuregulin 1 affects leptin levels, food intake and weight gain in normal-weight, but not obese, db/db mice

Ennequin

Caillaud

Chavanelle

et al. 2015

Diabetes & Metabolism

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Aim. -Studies in vitro have highlighted the potential involvement of neuregulin 1 (NRG1) in the regulation of energy metabolism. This effect has also been suggested in vivo, as intracerebroventricular injection of NRG1 reduces food intakes and weight gain in rodents. Thus, it was hypothesised that NRG1 might affect serum leptin levels in mice.Methods. -Weight, food intakes, energy expenditure, spontaneous physical activity and serum leptin levels were evaluated in normal-weight C57BL/6JRJ mice following intraperitoneal administration of NRG1 (50 g/kg, three times/week) or saline for 8 weeks. Based on the results of this first experiment, leptin-resistant obese db/db mice were then given NRG1 for 8 weeks.Results. -Leptin serum concentrations were six times higher in C57BL/6JRJ mice treated with NRG1 than in the animals given saline. NRG1 treatment also reduced weight gain by 10% and food intakes by 15% compared with saline treatment, while energy expenditure remained unchanged. In db/db mice, serum leptin concentrations, weight gain, food intakes, energy expenditure and spontaneous physical activity were not altered by NRG1 treatment.Conclusion. -The decrease in food intakes and weight gain associated with NRG1 treatment in C57BL/6JRJ mice may be partly explained by increased leptin levels, whereas db/db mice were not affected by the treatment, suggesting resistance to NRG1 in this pathological state.

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

Cited by 105 publications

References 47 publications

Cellular and molecular crosstalk between leptin receptor and estrogen receptor-α in breast cancer: molecular basis for a novel therapeutic setting

Cellular and molecular crosstalk between leptin receptor and estrogen receptor-α in breast cancer: molecular basis for a novel therapeutic setting

Leptin promotes the proliferation and migration of human breast cancer through the extracellular-signal regulated kinase pathway

Neuregulin 1 affects leptin levels, food intake and weight gain in normal-weight, but not obese, db/db mice

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