title: Pro-nerve growth factor induces autocrine stimulation of breast cancer cell invasion through tropomyosin-related kinase A (TrkA) and sortilin protein.
abstract: The precursor of nerve growth factor (proNGF) has been described as a biologically active polypeptide able to induce apoptosis in neuronal cells, via the neurotrophin receptor p75(NTR) and the sortilin receptor. Herein, it is shown that proNGF is produced and secreted by breast cancer cells, stimulating their invasion. Using Western blotting and mass spectrometry, proNGF was detected in a panel of breast cancer cells as well as in their conditioned media. Immunohistochemical analysis indicated an overproduction of proNGF in breast tumors, when compared with benign and normal breast biopsies, and a relationship to lymph node invasion in ductal carcinomas. Interestingly, siRNA against proNGF induced a decrease of breast cancer cell invasion that was restored by the addition of non-cleavable proNGF. The activation of TrkA, Akt, and Src, but not the MAP kinases, was observed. In addition, the proNGF invasive effect was inhibited by the Trk pharmacological inhibitor K252a, a kinase-dead TrkA, and siRNA against TrkA sortilin, neurotensin, whereas siRNA against p75(NTR) and the MAP kinase inhibitor PD98059 had no impact. These data reveal the existence of an autocrine loop stimulated by proNGF and mediated by TrkA and sortilin, with the activation of Akt and Src, for the stimulation of breast cancer cell invasion.
authors: INSERM U908 Growth Factor Signaling in Breast Cancer, University of Lille,Villeneuve d’Ascq 59655, France.
authors: Yohann
authors: Y
authors: Demont
authors: Cyril
authors: C
authors: Corbet
authors: Adeline
authors: A
authors: Page
authors: Yasemin
authors: Y
authors: Ataman-Önal
authors: Genevieve
authors: G
authors: Choquet-Kastylevsky
authors: Ingrid
authors: I
authors: Fliniaux
authors: Xuefen
authors: X
authors: Le Bourhis
authors: Robert-Alain
authors: RA
authors: Toillon
authors: Ralph A
authors: RA
authors: Bradshaw
authors: Hubert
authors: H
authors: Hondermarck
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000378:metabolism*; D019898:Autocrine Communication; D001706:Biopsy; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002227:Carbazoles / Q000494:pharmacology; D044584:Carcinoma, Ductal / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D026121:Indole Alkaloids / Q000494:pharmacology; D008207:Lymphatic Metastasis; D009361:Neoplasm Invasiveness; D020932:Nerve Growth Factor / Q000235:genetics / Q000378:metabolism*; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D020917:Receptor, trkA / Q000235:genetics / Q000378:metabolism*; D017475:Receptors, Nerve Growth Factor / Q000235:genetics / Q000378:metabolism; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism; D000099183:Sortilin
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D002227:Carbazoles; D004791:Enzyme Inhibitors; D026121:Indole Alkaloids; D020932:Nerve Growth Factor; D011498:Protein Precursors; D051057:Proto-Oncogene Proteins c-akt; D020917:Receptor, trkA; D017475:Receptors, Nerve Growth Factor; D019061:src-Family Kinases; D000099183:Sortilin; C061397:pro-nerve growth factor, human; C049985:staurosporine aglycone