title: Pharmacological inhibition of Rac1-PAK1 axis restores tamoxifen sensitivity in human resistant breast cancer cells.
abstract: 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 signaling pathways play a key role in tamoxifen resistance, being upregulation of Rac1-PAK1 signaling pathway one of the most important. Here, we report the development of the breast cancer cell model MCF7::C1199 having Rac1 enhanced activity with the aim of evaluating the role of Rac1 in acquired endocrine resistance. These cells not only showed distinctive features of Rac1-regulated process as increased migration and proliferation rates, but also showed 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 phosphorylation levels of estrogen receptor at Ser305, a key phosphorylation site involved in tamoxifen resistance. Finally, we evaluated 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 decreased estrogen receptor phospho-Ser305 levels. Since combination schemes of novel targeted agents with endocrine therapy could be potential new strategies to restore tamoxifen sensibility, these results show that inhibition of Rac1-PAK1 signaling pathway may provides benefits to revert resistance mechanisms in endocrine therapies.
authors.affiliation: Laboratory of Molecular Oncology, National University of Quilmes, Buenos Aires, Argentina.
authors.forename: N
authors.initials: N
authors.lastname: Gonzalez
authors.affiliation: Laboratory of Molecular Oncology, National University of Quilmes, Buenos Aires, Argentina.
authors.forename: G A
authors.initials: GA
authors.lastname: Cardama
authors.affiliation: Laboratory of Organic Synthesis, Center of Research and Development in Chemistry, National Institute of Industrial Technology (INTI), San Martín, Argentina.
authors.forename: M J
authors.initials: MJ
authors.lastname: Comin
authors.affiliation: Laboratory of Molecular Oncology, National University of Quilmes, Buenos Aires, Argentina.
authors.forename: V I
authors.initials: VI
authors.lastname: Segatori
authors.affiliation: Laboratory of Molecular Oncology, National University of Quilmes, Buenos Aires, Argentina.
authors.forename: M
authors.initials: M
authors.lastname: Pifano
authors.affiliation: Laboratory of Molecular Oncology, National University of Quilmes, Buenos Aires, Argentina; National Council of Scientific and Technical Research (CONICET), Buenos Aires, Argentina.
authors.forename: D F
authors.initials: DF
authors.lastname: Alonso
authors.affiliation: Laboratory of Molecular Oncology, National University of Quilmes, Buenos Aires, Argentina; National Council of Scientific and Technical Research (CONICET), Buenos Aires, Argentina. Electronic address: degomez@unq.edu.ar.
authors.forename: D E
authors.initials: DE
authors.lastname: Gomez
authors.affiliation: Laboratory of Molecular Oncology, National University of Quilmes, Buenos Aires, Argentina; National Council of Scientific and Technical Research (CONICET), Buenos Aires, Argentina.
authors.forename: P L
authors.initials: PL
authors.lastname: Menna
mesh_terms: D001943:Breast Neoplasms / Q000201:enzymology* / Q000473:pathology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004967:Estrogens / Q000494:pharmacology; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D008954:Models, Biological; D010641:Phenotype; D010766:Phosphorylation / Q000187:drug effects; D010768:Phosphoserine / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D013629:Tamoxifen / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects; D054462:p21-Activated Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D004967:Estrogens; D047428:Protein Kinase Inhibitors; D013629:Tamoxifen; D010768:Phosphoserine; D054462:p21-Activated Kinases; D020830:rac1 GTP-Binding Protein
keywords: Breast cancer; Estrogen receptor; Hormone-independence; Protein kinase; Small GTPases