Peer-Reviewed Journal Details
Mandatory Fields
Chakravarthy, R,Mnich, K,Gorman, AM
2016
September
Biochemical And Biophysical Research Communications
Nerve growth factor (NGF)-mediated regulation of p75(NTR) expression contributes to chemotherapeutic resistance in triple negative breast cancer cells
Published
Optional Fields
Apoptosis Breast cancer cells Nerve growth factor (NGF) p75 neurotrophin receptor (p75(NTR)) P75 NEUROTROPHIN RECEPTOR INTRACELLULAR DOMAIN THERAPEUTIC TARGET SIGNALING PATHWAYS ACTIVATION SURVIVAL NEURONS TRANSCRIPTION PATTERNS CLEAVAGE
478
1541
1547
Triple negative breast cancer [TNBC] cells are reported to secrete the neurotrophin nerve growth factor [NGF] and express its receptors, p75 neurotrophin receptor [p75(NTR)] and TrkA, leading to NGF-activated pro-survival autocrine signaling. This provides a rationale for NGF as a potential therapeutic target for TNBC. Here we show that exposure of TNBC cells to NGF leads to increased levels of p75(NTR), which was diminished by NGF-neutralizing antibody or NGF inhibitors [Ro 08-2750 and Y1086]. NGF-mediated increase in p75(NTR) levels were partly due to increased transcription and partly due to inhibition of proteolytic processing of p75(NTR). In contrast, proNGF caused a decrease in p75(NTR) levels. Functionally, NGF-induced increase in p75(NTR) caused a decrease in the sensitivity of TNBC cells to apoptosis induction. In contrast, knock-down of p75(NTR) using shRNA or small molecule inhibition of NGF-p75(NTR) interaction [using Ro 08-2750] sensitized TNBC cells to drug-induced apoptosis. In patient samples, the expression of NGF and NGFR [the p75(NTR) gene] mRNA are positively correlated in several subtypes of breast cancer, including basal-like breast cancer. Together these data suggest a positive feedback loop through which NGF-mediated upregulation of p75(NTR) can contribute to the chemo-resistance of TNBC cells. (C) 2016 Elsevier Inc. All rights reserved.
10.1016/j.bbrc.2016.08.149
Grant Details
Publication Themes