Artículo
Pharmacological inhibition of Rac1-PAK1 axis restores tamoxifen sensitivity in human resistant breast cancer cells
Gonzalez, N.; Cardama, Georgina Alexandra
; Comin, Maria Julieta
; Segatori, Valeria Inés
; Pifano, Marina
; Alonso, Daniel Fernando
; Gomez, D. E.; Lorenzano Menna, Pablo
Fecha de publicación:
01/2017
Editorial:
Elsevier Science Inc
Revista:
Cellular Signalling
ISSN:
0898-6568
Idioma:
Inglés
Tipo de recurso:
Artículo publicado
Clasificación temática:
Resumen
Tamoxifen is a standard endocrine therapy for estrogen receptor positive breast cancer patients. Despite its success,development of resistance mechanisms is still a serious clinical problem. Deregulation of survival signalingpathways play a key role in tamoxifen resistance, being upregulation of Rac1-PAK1 signaling pathway one of themost important. Here, we report the development of the breast cancer cell model MCF7::C1199 having Rac1 enhancedactivity with the aim of evaluating the role of Rac1 in acquired endocrine resistance. These cells not onlyshowed distinctive features of Rac1-regulated process as increased migration and proliferation rates, but alsoshowed that upregulation of Rac1 activity triggered a hormonal-independent and tamoxifen resistant phenotype.We also demonstrated that PAK1 activity increases in response to Tamoxifen, increasing phosphorylationlevels of estrogen receptor at Ser305, a key phosphorylation site involved in tamoxifen resistance. Finally, weevaluated the effect of 1A-116, a specific Rac1 inhibitor developed by our group, in tamoxifen-resistant cells.1A-116 effectively restored tamoxifen anti-proliferative effects, switched off PAK1 activity and decreasedestrogen receptor phospho-Ser305 levels. Since combination schemes of novel targeted agents with endocrinetherapy could be potential new strategies to restore tamoxifen sensibility, these results show that inhibition ofRac1-PAK1 signaling pathway may provides benefits to revert resistance mechanisms in endocrine therapies.
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Articulos de SEDE CENTRAL
Citación
Gonzalez, N.; Cardama, Georgina Alexandra; Comin, Maria Julieta; Segatori, Valeria Inés; Pifano, Marina; et al.; Pharmacological inhibition of Rac1-PAK1 axis restores tamoxifen sensitivity in human resistant breast cancer cells; Elsevier Science Inc; Cellular Signalling; 30; 1-2017; 154-161
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