Activation of EGFR, HER2 and HER3 by neurotensin/neurotensin receptor 1 renders breast tumors aggressive yet highly responsive to lapatinib and metformin in mice

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 regulation induces overexpression and activation of EGFR in HCC and restores response to erlotinib and sorafenib

“…In our hands, the PLC/PRF5 cells were highly invasive, overexpression of NTSR1 did not markedly change these characteristics. Collectively, these data suggest that the NTS and NTSR1 promote the invasiveness and migration of HCC cells, and corroborate the data previously published for HCC [32] and breast cancer [6].…”

“…NTS/NTSR1 would therefore be expected to be a mediator between the Wnt/b-catenin pathway and EGFR signaling. These regulations enhance invasive and migratory cellular effects and consequently metastatic processes in HCC cells, and are similar to results in breast, lung cancer, and neck squamous cell carcinomas [6,21,33]. Even the endpoint effects are similar between the carcinomas, though the mechanisms sustaining these effects are different, involving diverse metalloproteinases, epidermal growth factor receptors and their ligands [6,33].…”

“…NTS/NTSR1 complex is known to potentiate EGF signaling [2,6,33,34]. We investigated the possible relationship between NTSR1 and EGFR regulation.…”

“…In addition, it was shown that the sustained stimulation Abbreviation: NTS, neurotensin; NTSR1, neurotensin receptor 1; HCC, hepatocellular carcinoma; HBV, hepatitis B virus; HCV, hepatitis C virus; EGF, epidermal growth factor; EGFR, epidermal growth factor receptor; ERK, extracellular signalregulated kinases; PKB, protein kinase B; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor; PDGFR, platelet-derived growth factor receptor; RT-PCR, reverse transcriptase-polymerase reaction; OS, overall survival. 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 of NTSR1 generated autocrine regulation of epidermal growth factor receptors, producing cell hyper-sensitivity to tyrosine kinase inhibitors, as is the case for erlotinib in lung cancer or lapatinib in breast cancer [6,33]. NTS is expressed in the fetal human liver but repressed in the normal adult liver.…”

Neurotensin (NTS) and its receptor (NTSR1) causes EGFR, HER2 and HER3 over-expression and their autocrine/paracrine activation in lung tumors, confirming responsiveness to erlotinib

“…The breast cells and the experimental tumors expressing NTS also displayed an increase in EGFR, HER2, and HER3 expression and activation. The latter effect was correlated with an increase of Hb-EGF, Neuregulin 2, and MMP9 [55]. …”