TY - JOUR
T1 - Substance P Autocrine Signaling Contributes to Persistent HER2 Activation That Drives Malignant Progression and Drug Resistance in Breast Cancer
AU - Garcia-Recio, Susana
AU - Fuster, Gemma
AU - Fernandez-Nogueira, Patricia
AU - Pastor-Arroyo, Eva M.
AU - Park, So Yeon
AU - Mayordomo, Cristina
AU - Ametller, Elisabet
AU - Mancino, Mario
AU - Gonzalez-Farre, Xavier
AU - Russnes, Hege G.
AU - Engel, Pablo
AU - Costamagna, Domiziana
AU - Fernandez, Pedro L.
AU - Gascon, Pedro
AU - Almendro, Vanessa
PY - 2013/11/1
Y1 - 2013/11/1
N2 - ERBB receptor transmodulation by heterologous G-protein-coupled receptors (GPCR) generates functional diversity in signal transduction. Tachykinins are neuropeptides and proinflammatory cytokines that promote cell survival and cancer progression by activating several GPCRs. In this work, we found that the pain-associated tachykinin Substance P (SP) contributes to persistent transmodulation of the ERBB receptors, EGFR and HER2, in breast cancer, acting to enhance malignancy and therapeutic resistance. SP and its high-affinity receptor NK-1R were highly expressed in HER2(+) primary breast tumors (relative to the luminal and triple-negative subtypes) and were overall correlated with poor prognosis factors. In breast cancer cell lines and primary cultures derived from breast cancer samples, we found that SP could activate HER2. Conversely, RNA interference-mediated attenuation of NK-1R, or its chemical inhibition, or suppression of overall GPCR-mediated signaling, all strongly decreased steady-state expression of EGFR and HER2, establishing that their basal activity relied upon transdirectional activation by GPCR. Thus, SP exposure affected cellular responses to anti-ERBB therapies. Our work reveals an important oncogenic cooperation between NK-1R and HER2, thereby adding a novel link between inflammation and cancer progression that may be targetable by SP antagonists that have been clinically explored. (C)2013 AACR.
AB - ERBB receptor transmodulation by heterologous G-protein-coupled receptors (GPCR) generates functional diversity in signal transduction. Tachykinins are neuropeptides and proinflammatory cytokines that promote cell survival and cancer progression by activating several GPCRs. In this work, we found that the pain-associated tachykinin Substance P (SP) contributes to persistent transmodulation of the ERBB receptors, EGFR and HER2, in breast cancer, acting to enhance malignancy and therapeutic resistance. SP and its high-affinity receptor NK-1R were highly expressed in HER2(+) primary breast tumors (relative to the luminal and triple-negative subtypes) and were overall correlated with poor prognosis factors. In breast cancer cell lines and primary cultures derived from breast cancer samples, we found that SP could activate HER2. Conversely, RNA interference-mediated attenuation of NK-1R, or its chemical inhibition, or suppression of overall GPCR-mediated signaling, all strongly decreased steady-state expression of EGFR and HER2, establishing that their basal activity relied upon transdirectional activation by GPCR. Thus, SP exposure affected cellular responses to anti-ERBB therapies. Our work reveals an important oncogenic cooperation between NK-1R and HER2, thereby adding a novel link between inflammation and cancer progression that may be targetable by SP antagonists that have been clinically explored. (C)2013 AACR.
KW - PROTEIN-COUPLED RECEPTORS
KW - TRANSACTIVATION
KW - TACHYKININS
KW - EXPRESSION
KW - TISSUE
KW - CELLS
KW - SRC
KW - PHOSPHORYLATION
KW - INFLAMMATION
KW - STIMULATION
U2 - 10.1158/0008-5472.CAN-12-4573
DO - 10.1158/0008-5472.CAN-12-4573
M3 - Article
VL - 73
SP - 6424
EP - 6434
IS - 21
ER -