leptin and Carcinoma--Lobular

Breast cancer is the most common in women worldwide, with some 5-10% of all cases due to inherited mutations of BRCA1 and BRCA2 genes. Obesity, hormone therapy and use of alcohol are possible causes and over-expression of leptin in adipose tissue may also play a role. Normally surgery, radiation therapy and chemotherapy allow a good prognosis where screening measures are in place. New hope in treatment measures include adjuvant therapy, neoadjuvant therapy, and introduction of mono-clonal antibodies and enzyme inhibitors.

Topics: Adipose Tissue; Alcohol Drinking; Breast Neoplasms; Carcinoma, Ductal, Breast; Carcinoma, Lobular; Chemotherapy, Adjuvant; Estrogen Replacement Therapy; Female; Genes, BRCA1; Genes, BRCA2; Humans; Leptin; Mastectomy; Neoadjuvant Therapy; Obesity; Radiotherapy, Adjuvant; Risk Factors; Sedentary Behavior; Selective Estrogen Receptor Modulators

Adipokines in the tumor microenvironment may contribute to cancer growth. We hypothesized that peritumoral fat can be a source of lipid-derived energy for tumors by increasing adipose triglyceride lipase (ATGL)-mediated lipolysis and down-regulating a negative regulator of adipogenesis, pigment epithelium-derived factor (PEDF).. In a pilot study, tissue from mastectomies (n = 19) was collected from sites both adjacent (peritumoral) and distant to the tumor for comparison of ATGL, PEDF, and leptin expression levels using immunohistochemistry. Statistical analysis was performed by Student's t test to determine significance.. Mean tumor size was 2.4 cm, and 10 (59 %) patients had tumor-positive nodes. Mean body mass index (BMI) was 28.1 kg/m(2). ATGL expression was significantly increased in obese patients (BMI ≥ 30 kg/m(2)) compared with the nonobese group (P < 0.04). Leptin expression was increased in the peritumoral stroma of obese patients compared with distant sites (P = 0.03). Peritumoral PEDF and the leptin/PEDF ratio were significantly affected by tumor size and node status. Tumors ≥ 2 cm had lower peritumoral stromal expression of PEDF than tumors <2 cm (P = 0.01). In node-positive cases, expression of PEDF was significantly decreased in the peritumoral stroma compared with node-negative cases (1.22 vs. 1.80, P < 0.04). The leptin/PEDF ratio was markedly elevated in the peritumoral region of node-positive cases versus node-negative cases (2.17 vs. 1.18, P < 0.001).. Peritumoral expression of adipokines was altered in both obesity and more advanced breast tumors, suggesting a role for adipokines in enhancing tumor growth. Future studies should focus on the use of adipokines as biomarkers.

Topics: Adipokines; Adipose Tissue; Adult; Biomarkers, Tumor; Body Mass Index; Breast Neoplasms; Carcinoma, Ductal, Breast; Carcinoma, Intraductal, Noninfiltrating; Carcinoma, Lobular; Cell Proliferation; Eye Proteins; Fatty Acids; Female; Follow-Up Studies; Humans; Immunoenzyme Techniques; Leptin; Lipase; Lymphatic Metastasis; Mastectomy; Middle Aged; Neoplasm Staging; Nerve Growth Factors; Obesity; Pilot Projects; Prognosis; Serpins; Survival Rate; Tumor Cells, Cultured

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-alpha (ERalpha). To this aim, we utilized two human breast cancer cell lines, one ERalpha-positive cell line (MCF 7) and the other ERalpha-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 ERalpha 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 gene-silencing siRNA. These data suggest that there is a bidirectional communication between LepR and ERalpha, 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 ERalpha. In conclusion, this study suggests a crosstalk between LepR and ERalpha, and could envisage novel therapeutic settings aimed at targeting the LepR in breast cancers.

Topics: Adult; Aged; Aged, 80 and over; Blotting, Western; Breast; Breast Neoplasms; Carcinoma, Ductal, Breast; Carcinoma, Lobular; Cell Death; Cell Line, Tumor; Cell Proliferation; Cells, Cultured; Dose-Response Relationship, Drug; Estrogen Receptor alpha; Female; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; Leptin; Middle Aged; Mitogen-Activated Protein Kinase 3; Neoplasm Staging; Phosphorylation; Receptors, Leptin; Signal Transduction; STAT Transcription Factors; Statistics, Nonparametric