The Neurotensin Receptor-1 Pathway Contributes to Human Ductal Breast Cancer Progression

BACKGROUND: The neurotensin (NTS) and its specific high affinity G protein coupled receptor, the NT1 receptor (NTSR1), are considered to be a good candidate for one of the factors implicated in neoplastic progression. In breast cancer cells, functionally expressed NT1 receptor coordinates a series of transforming functions including cellular migration and invasion. METHODS AND RESULTS: we investigated the expression of NTS and NTSR1 in normal human breast tissue and in invasive ductal breast carcinomas (IDCs) by immunohistochemistry and RT-PCR. NTS is expressed and up-regulated by estrogen in normal epithelial breast cells. NTS is also found expressed in the ductal and invasive components of IDCs. The high expression of NTSR1 is associated with the SBR grade, the size of the tumor, and the number of metastatic lymph nodes. Furthermore, the NTSR1 high expression is an independent factor of prognosis associated with the death of patients. CONCLUSION: these data support the activation of neurotensinergic deleterious pathways in breast cancer progression

Increased Infiltration of Macrophages in Omental Adipose Tissue Is Associated With Marked Hepatic Lesions in Morbid Human Obesity

International audienceIn human obesity, white adipose tissue (WAT) is enriched in macrophages. How macrophage infiltration in WAT contributes to the complications of obesity is unknown. This study tested the hypothesis that recruitment of macrophages in omental WAT is associated with hepatic damage in obese patients. Paired biopsies of subcutaneous and omental WAT and a liver biopsy were collected during gastric surgery in 46 obese women and 9 obese men (BMI 47.9 0.93 kg/m 2). The number of HAM56 macrophages in WAT was quantified microscopically, and correlations with clinical and biological parameters and histological liver pathology were investigated. There were twice as many macrophages in omental as in subcutaneous WAT (P < 0.0001). After adjustment for age, omental WAT macrophage infiltration was correlated to fasting glucose and insulin, quantitative insulin sensitivity check index, triglycerides, aspartate aminotransferase (AST), and-glutamyltranspeptidase. We propose an easy equation to estimate the amount of macrophages in omental WAT. Increased macrophage accumulation specifically in omental WAT was associated with hepatic fibroinflammatory lesions (P 0.01). The best predictive model for the severity of hepatic damage includes adiponectinemia, AST, and omental WAT macro-phages. These data suggest that the presence of macrophages in omental WAT participates in the cellular mechanisms favoring hepatic fibroinflammatory lesions in obese patients

Neurotensin expression in normal breast tissue.

<p>a) <i>Left</i>, one µg of total RNA from HBEC or whole gland were reverse-transcribed and a PCR experiment specific for NTS was performed. <i>Right</i>, <i>o</i>ne µg of total RNA from HBEC cells (control, treated with 10 nM estradiol (E2) with or without 1 µM ICI 182780) was reverse-transcribed. A PCR experiment was performed using specific primers for NTS and GAPDH. b) Normal duct exposed to NTS antibody at 1/500 dilution (1), after pre-incubation with the antigen peptide for 2 h at 10 nM (2), or without primary antibody (3), and lobule exposed to NTS antibody (4). Normal tissue exposed to NTS antibody at 1/500 dilution adjacent to tumor duct (5), lobule (6). The original magnification was 200×.</p

Patients clinical characteristics.

<p>SBR; Scarff Bloom and Richardson, n = number of patients, SD = standard deviation.</p

NTSR1 expression in IDCs and global survival duration.

<p>Kaplan-Maier analysis for global survival duration in both groups with low (<80%) and high (≥80%) NTSR1 expression. Probability of overall death for patients with high NTSR1 expression (n = 38) versus patients with low NTSR1 expression (n = 68).</p

Prognosis factors and deaths stratified by NT-1 receptor expression in the invasive component of IDCs.

<p>Prognosis factors and deaths stratified by NT-1 receptor expression in the invasive component of IDCs.</p

Neurotensin expression in IDCs.

<p>a) NTS immunohistochemistry was performed on IDCs, ductal (1) and invasive (2) components, magnification 200× for (1) and 400× for (2). b) NTS and NTSR1 transcripts in IDCs. One µg of total RNA from 11 patients with IDCs were reverse-transcribed, and specific PCR was performed for NTS, NT-1 receptor, or GAPDH (control). The SBR grade is indicated below each line. c) Example of NTS and NTSR1 regional co-localization by immunohistochemistry for NTS (right) and NTSR1 (left) at the original magnification 400×.</p

Prognosis factors and deaths stratified by NT expression in the ductal and invasive components of IDCs.

<p>Prognosis factors and deaths stratified by NT expression in the ductal and invasive components of IDCs.</p

Correlation of the subpopulation co-expressing NT and NT1 receptor with the major prognosis factors.

<p>Correlation of the subpopulation co-expressing NT and NT1 receptor with the major prognosis factors.</p