Overexpression of p75(NTR) increases survival of breast cancer cells through p21(waf1).
The p75 neurotrophin receptor (p75(NTR)) plays a critical role in various neuronal and non-neuronal cell types by regulating cell survival, differentiation and proliferation. To evaluate the influence of p75(NTR) in breast cancer development, we have established and characterized breast cancer cells which stably overexpress p75(NTR). We showed that p75(NTR) overexpression per se promoted cell survival to apoptogens with a concomitant slowdown of cell growth. The pro-survival effect is associated with an increased expression of the inhibitor of apoptosis protein-1 (c-IAP1), a decrease of TRAIL-induced cleavage of PARP, procaspase 9 and procaspase 3, and a decrease of cytochrome C release from the mitochondria. The anti-proliferative effect is due to a cell accumulation in G0/G1, associated with a decrease of Rb phosphorylation and an increase of p21(waf1). Interestingly, inhibition of p21(waf1) with siRNA not only restores proliferation but also abolishes the pro-survival effect of p75(NTR), indicating the key role of p21(waf1) in the biological functions of p75(NTR). Finally, using a SCID mice xenograft model, we showed that p75(NTR) overexpression favors tumor growth and strongly increases tumor resistance to anti-tumoral treatment. Together, our findings suggest that p75(NTR) overexpression in breast tumor cells could favor tumor survival and contribute to tumor resistance to drugs. This provides a rationale to consider p75(NTR) as a potential target for the future design of innovative therapeutic strategies.
Verbeke
Stéphanie
S
INSERM U908, F-59650 Villeneuve d'Ascq, France.
Meignan
Samuel
S
Lagadec
Chann
C
Germain
Emmanuelle
E
Hondermarck
Hubert
H
Adriaenssens
Eric
E
Le Bourhis
Xuefen
X
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000473:pathology*; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000502:physiology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism* / Q000494:pharmacology; D003574:Cytochrome c Group / Q000378:metabolism; D005260:Female; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D020800:Receptor, Nerve Growth Factor / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays / Q000379:methods
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D003574:Cytochrome c Group; D051034:Inhibitor of Apoptosis Proteins; D020800:Receptor, Nerve Growth Factor; C076615:cytochrome c''; D053148:Caspase 3; D053453:Caspase 9