Inhibition of the Rho GTPase, Rac1, decreases estrogen receptor levels and is a novel therapeutic strategy in breast cancer.
Rac1, a Rho GTPase, modulates diverse cellular processes and is hyperactive in some cancers. Estrogen receptor-alpha (ERα) in concert with intracellular signaling pathways regulates genes associated with cell proliferation, tumor development, and breast cancer cell survival. Therefore, we examined the possibility of Rac1 and ERα crosstalk in breast cancer cells. We found that Rac1 enhanced ERα transcriptional activity in breast cancer cells. Vav3, a Rho guanine nucleotide exchange factor that activates Rac1, was an upstream mediator, and P21/Cdc42/Rac1 activating kinase-1 (Pak-1) was a downstream effector of Rac1 enhancement of ERα activity. These results suggest that Rac1 may prove to be a therapeutic target. To test this hypothesis, we used a small molecule Rac inhibitor, EHT 1864, and found that EHT 1864 inhibited ERα transcriptional activity. Furthermore, EHT 1864 inhibited estrogen-induced cell proliferation in breast cancer cells and decreased tamoxifen-resistant breast cancer cell growth. EHT 1864 decreased activity of the promoter of the ERα gene resulting in down-regulation of ERα mRNA and protein levels. Therefore, ERα down-regulation by EHT 1864 is the likely mechanism of EHT 1864-mediated inhibition of ERα activity and estrogen-stimulated breast cancer cell proliferation. Since ERα plays a critical role in the pathogenesis of breast cancer and the Rac inhibitor EHT 1864 down-regulates ERα expression and breast cancer cell proliferation, further investigation of the therapeutic potential of Rac1 targeting in the treatment of breast cancer is warranted.
Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, 1600 Northwest 10th Avenue (R-189), Miami, Florida 33136, USA.
Adena E
AE
Rosenblatt
Maria Ines
MI
Garcia
Leah
L
Lyons
Yingqiu
Y
Xie
Carol
C
Maiorino
Laurent
L
Désiré
Joyce
J
Slingerland
Kerry L
KL
Burnstein
D015153:Blotting, Western; D001943:Breast Neoplasms / Q000201:enzymology / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005260:Female; D006801:Humans; D051567:Proto-Oncogene Proteins c-vav / Q000378:metabolism; D011753:Pyrones / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D012313:RNA / Q000737:chemistry; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic; D054462:p21-Activated Kinases / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism
C506907:EHT 1864; C506487:ESR1 protein, human; D004791:Enzyme Inhibitors; D047628:Estrogen Receptor alpha; D051567:Proto-Oncogene Proteins c-vav; D011753:Pyrones; D011804:Quinolines; C107953:RAC1 protein, human; C496621:VAV3 protein, human; D012313:RNA; D054462:p21-Activated Kinases; D020830:rac1 GTP-Binding Protein; D020741:rho GTP-Binding Proteins