No abstract

A present challenge in breast oncology research is to identify therapeutical targets which could impact tumor progression. Neurotensin (NTS) and its high affinity receptor (NTSR1) are up regulated in 20% of breast cancers, and NTSR1 overexpression was shown to predict a poor prognosis for 5 year overall survival in invasive breast carcinomas. Interactions between NTS and NTSR1 induce pro-oncogenic biological effects associated with neoplastic processes and tumor progression. Here, we depict the cellular mechanisms activated by NTS, and contributing to breast cancer cell aggressiveness.We show that neurotensin (NTS) and its high affinity receptor (NTSR1) contribute to the enhancement of experimental tumor growth and metastasis emergence in an experimental mice model. This effect ensued following EGFR, HER2, and HER3 over-expression and autocrine activation and was associated with an increase of metalloproteinase MMP9, HB-EGF and Neuregulin 2 in the culture media. EGFR over expression ensued in a more intense response to EGF on cellular migration and invasion. Accordingly, lapatinib, an EGFR/HER2 tyrosine kinase inhibitor, as well as metformin, reduced the tumor growth of cells overexpressing NTS and NTSR1. All cellular effects, such as adherence, migration, invasion, altered by NTS/NTSR1 were abolished by a specific NTSR1 antagonist. A strong statistical correlation between NTS-NTSR1-and HER3 (p< 0.0001) as well as NTS-NTSR1-and HER3- HER2 (p< 0.001) expression was found in human breast tumors.Expression of NTS/NTSR1 on breast tumoral cells creates a cellular context associated with cancer aggressiveness by enhancing epidermal growth factor receptor activity. We propose the use of labeled NTS/NTSR1 complexes to enlarge the population eligible for therapy targeting HERs tyrosine kinase inhibitor or HER2 overexpression.

Neurotensin (NTS) is a 13 amino acid peptide, exerting hormonal and neurocrine regulation within the gastrointestinal tract to globally facilitate nutriment digestion. NTS action is mainly mediated by the high affinity G protein coupled neurotensin receptor, NTSR1. Abnormal expression of NTSR1 occurs during the early stages of cell transformation in relation with the deregulation of the Wnt/beta catenin pathway. Consequently, the oncogenic effects previously described for NTS in different types of cancer cells could presumably contribute to tumor progression. In order to establish this concept, we observed that NTS and NTSR1 were concomitantly expressed in human breast ductal carcinomas and lung adenocarcinomas. NTSR1 was found to be an independent prognostic marker in lung and breast clinical studies. Cellular models were developed in which NTS or NTSR1 was either abolished by sh-RNA or over-expressed. In experimental tumors using both models, active NTS autocrine or paracrine regulation caused the enhancement of tumor size and metastasis emergence when compared to those having poor expression of NTS or NTSR1. In vitro studies, confirmed that NTS enhancement of cellular growth, adherence, motility and invasion occurred through the activation of PKC, ERK 1/2 pathways, and by interfering with the network of epidermal growth factor tyrosine receptors, as EGFR, HER2, and HER3 expression and activation were increased. The use of NTSR1 specific antagonist and neutralizing NTS antibody confirmed the contribution of NTS in cellular oncogenic effect implicated in each step of cancer progression. Additionally, the activation of metalloprotease induced by NTS contributed to the release to EGF-like ligand. Our results suggest that the activation of the NTSR1 pathway causes an acceleration of the oncogenesis process within preexisting tumors by the up regulation of the three majors epidermal growth factor tyrosine receptors and the formation of autocrine stimulation of the HERs system. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1116. doi:10.1158/1538-7445.AM2011-1116