Brain-Derived Neurotrophic Factor and Neurotrophin-4/5 Are Expressed in Breast Cancer and Can Be Targeted to Inhibit Tumor Cell Survival

Vanhecke, Elsa; Adriaenssens, Éric; Verbeke, Stéphanie; Meignan, Samuel; Germain, Emmanuelle; Berteaux, Nathalie; Nurcombe, Victor; Bourhis, Xuefen Le; Hondermarck, Hubert

doi:10.1158/1078-0432.ccr-10-1890

Cited by 106 publications

(120 citation statements)

References 41 publications

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“…Mice inoculated with breast cancer cells and treated with antibodies against BDNF display slower tumor progression compared to mice treated with control antibodies (38). These results were recapitulated in a mouse model of uterine sarcoma (39) and neuroblastoma (40,41).…”

Section: Bdnf: a Governor Of Chemotherapeutic Sensitivitymentioning

confidence: 68%

BDNF: An Oncogene or Tumor Suppressor?

Radin

Patel

2017

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Section: Bdnf: a Governor Of Chemotherapeutic Sensitivitymentioning

confidence: 68%

BDNF: An Oncogene or Tumor Suppressor?

Radin

Patel

2017

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“…ProNGF production adds to the recently reported expression of brain-derived neurotrophic factor (BDNF) and neurotrophin-4/5 (NT-4/5), showing that neurotrophin family members and their receptors are generally involved in breast cancer (35). Brain-derived neurotrophic factor and NT-4/5 exhibit a different type of activity on breast cancer cells as they were found to stimulate tumor cell survival.…”

Section: Discussionmentioning

confidence: 93%

Pro-nerve Growth Factor Induces Autocrine Stimulation of Breast Cancer Cell Invasion through Tropomyosin-related Kinase A (TrkA) and Sortilin Protein

Demont

Corbet

Page

et al. 2012

Journal of Biological Chemistry

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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 noncleavable 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. Nerve growth factor (NGF),5 the prototypical member of the neurotrophin family of polypeptides, is essential for the survival and differentiation of central and peripheral neurons, and its role in the development and regeneration of the sympathetic and sensory nervous systems has been extensively described (1). NGF binds to the tropomyosin-related kinase A (TrkA) receptor, a tyrosine kinase receptor, and to the p75 neurotrophin receptor (p75 NTR ), a member of the tumor necrosis factor receptor family, to induce its neurotrophic effects. NGF is synthesized as a 25-kDa precursor protein, named proNGF, that yields the mature NGF polypeptide of 13.5 kDa and an inactive prosegment of 11.5 kDa, released from the N terminus intracellularly by furin, or extracellularly by plasmin as well as by several matrix metalloproteases (2). Importantly, proNGF can be secreted without being processed to mature NGF and can have its own biological effects (3). As more than just a source for NGF, proNGF was shown to induce neuronal death by apoptosis where mature NGF induced survival and differentiation (4, 5). For inducing its proapoptotic effect on neurons, proNGF forms a trimeric complex with two plasma membrane receptors: p75 NTR and sortilin (4). Sortilin, a 95-kDa type I receptor,

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“…Previous studies on breast and ovarian cancer cells have suggested that BDNF/TrkB stimulates cell survival and migration (20,22,23,25). BDNF is likely not to enhance viability since the BDNF/TrkB pathway is already activated at its optimal level by BDNF secreted from the cells as an autocrine factor.…”

Section: Discussionmentioning

confidence: 99%

“…In breast cancer, BDNF expression has been shown to be higher in tumor samples compared to non-neoplastic tissues, while BDNF transcript levels have been associated with unfavorable pathological parameters and adverse clinical outcomes (24). Moreover, BDNF has been shown to induce resistance to apoptosis in breast cancer cells, while injection of an anti-BDNF antibody has been proven to reduce the growth of breast tumors xenografted in mice (25). The present study aimed to explore the effects of GRPR and TrkB ligands on the viability of human breast, ovarian and cervical cancer cells in vitro.…”

Section: Introductionmentioning

confidence: 99%

Influence of GRPR and BDNF/TrkB signaling on the viability of breast and gynecologic cancer cells

Cornélio

Farias

Prusch

et al. 2012

Molecular and Clinical Oncology

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Abstract. Neuropeptide and neurotrophin receptors are increasingly important molecular targets in cancer. Scientific findings indicate that compounds blocking gastrin-releasing peptide receptors (GRPR) or tropomyosin receptor kinase (Trk) receptors are likely to have antiproliferative activities against cancer cells. The present study aimed to demonstrate that, in contrast to previous findings, GRPR activation reduces, whereas its blockade increases the viability of breast, ovarian and cervical cancer cell lines. However, consistent with previous studies, Trk inhibition was demonstrated to reduce the viability of these cells. MCF-7 (breast), OVCAR-3 (ovarian) and HeLa (cervical) human cancer cell lines were treated with GRP, the GRPR antagonists RC-3095 and RC-3940-II, brain-derived neurotrophic factor (BDNF) and the Trk antagonist K252α. Cell viability was measured by the MTT assay. Expression of GRPR and BDNF was confirmed with reverse transcription-polymerase chain reaction (RT-PCR). GRP reduced, whereas RC-3940-II enhanced the viability of the three cell lines. Treatment with K252α inhibited the viability of the cell lines, while BDNF increased the viability of OVCAR-3 cells. The results supported the hypothesis that GRPR and BDNF/TrkB signaling regulates cancer cell viability. Most importantly, these findings are the first to demonstrate that GRPR blockade can stimulate, rather than inhibits the viability of breast and gynecologic cancer cell lines.

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Brain-Derived Neurotrophic Factor and Neurotrophin-4/5 Are Expressed in Breast Cancer and Can Be Targeted to Inhibit Tumor Cell Survival

Cited by 106 publications

References 41 publications

BDNF: An Oncogene or Tumor Suppressor?

BDNF: An Oncogene or Tumor Suppressor?

Pro-nerve Growth Factor Induces Autocrine Stimulation of Breast Cancer Cell Invasion through Tropomyosin-related Kinase A (TrkA) and Sortilin Protein

Influence of GRPR and BDNF/TrkB signaling on the viability of breast and gynecologic cancer cells

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