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2013-11

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Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/120272

Substance P autocrine signaling contributes to persistent HER2 activation that drives malignant progression and drug resistance in breast cancer.

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https://doi.org/10.1158/0008-5472.CAN-12-4573

Resum

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.

Matèries

Càncer de mama, Genètica molecular, Teràpia genètica

Matèries (anglès)

Breast cancer, Molecular genetics, Gene therapy

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Articles publicats en revistes (Medicina)
Articles publicats en revistes (IDIBAPS: Institut d'investigacions Biomèdiques August Pi i Sunyer)

Citació

GARCIA RECIO, Susana, FUSTER ORELLANA, Gemma, FERNANDEZ-NOGUEIRA, Patricia, PASTOR ARROYO, Eva m., YEONG PARK, So, MAYORDOMO, Cristina, AMETLLER, Elisabet, MANCINO, Mario, GONZALEZ-FARRE, Xavier, RUSSNES, Hage g., ENGEL ROCAMORA, Pablo, COSTAMAGNA, Domiziana, FERNANDEZ, Pedro l., GASCÓN, Pere, ALMENDRO NAVARRO, Vanessa. Substance P autocrine signaling contributes to persistent HER2 activation that drives malignant progression and drug resistance in breast cancer.. _Cancer Research_. 2013. Vol. 73, núm. 21, pàgs. 6424-6434. [consulta: 24 de gener de 2026]. ISSN: 0008-5472. [Disponible a: https://hdl.handle.net/2445/120272]

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