Pharmacological inhibition of Rac1-PAK1 axis restores tamoxifen sensitivity in human resistant breast cancer cells

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.
Fil: Gonzalez, N.. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina
Fil: Cardama, Georgina Alexandra. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina