title: Nerve growth factor (NGF)-mediated regulation of p75(NTR) expression contributes to chemotherapeutic resistance in triple negative breast cancer cells.
abstract: 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.
authors: Apoptosis Research Centre, NUI, Galway, Ireland.
authors: Reka
authors: R
authors: Chakravarthy
authors: Apoptosis Research Centre, NUI, Galway, Ireland.
authors: Katarzyna
authors: K
authors: Mnich
authors: Apoptosis Research Centre, NUI, Galway, Ireland. Electronic address: Adrienne.gorman@nuigalway.ie.
authors: Adrienne M
authors: AM
authors: Gorman
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006801:Humans; D051379:Mice; D020932:Nerve Growth Factor / Q000494:pharmacology*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D017475:Receptors, Nerve Growth Factor / Q000378:metabolism*; D064726:Triple Negative Breast Neoplasms / Q000378:metabolism* / Q000473:pathology
chemical_list: C502240:NGF protein, human; C484065:NGFR protein, human; D009419:Nerve Tissue Proteins; D017475:Receptors, Nerve Growth Factor; D020932:Nerve Growth Factor
keywords: Apoptosis; Breast cancer cells; Nerve growth factor (NGF); p75 neurotrophin receptor (p75(NTR))