IKKepsilon phosphorylation of estrogen receptor alpha Ser-167 and contribution to tamoxifen resistance in breast cancer.
IKKepsilon has recently been identified as a breast cancer oncogene. Elevated levels of IKKepsilon are associated with cell survival and growth. Here, we show that IKKepsilon interacts with and phosphorylates estrogen receptor alpha (ERalpha) on serine 167 in vitro and in vivo. As a result, IKKepsilon induces ERalpha transactivation activity and enhances ERalpha binding to DNA. Cyclin D1, a major target of ERalpha, is transcriptionally up-regulated by IKKepsilon in a phospho-ERalpha-Ser-167-dependent manner. Further, overexpression of IKKepsilon induces tamoxifen resistance, whereas knockdown of IKKepsilon sensitizes cells to tamoxifen-induced cell death. These data suggest that ERalpha is a bona fide substrate of IKKepsilon and IKKepsilon plays an important role in tamoxifen resistance. Thus, IKKepsilon represents a critical therapeutic target in breast cancer.
Guo
Jian-Ping
JP
From the Departments of Molecular Oncology, H. Lee Moffitt Cancer Center, Tampa, Florida 33612.
Shu
Shao-Kun
SK
From the Departments of Molecular Oncology, H. Lee Moffitt Cancer Center, Tampa, Florida 33612.
Esposito
Nicole N
NN
Departments of Pathology, H. Lee Moffitt Cancer Center, Tampa, Florida 33612.
Coppola
Domenico
D
Departments of Pathology, H. Lee Moffitt Cancer Center, Tampa, Florida 33612.
Koomen
John M
JM
From the Departments of Molecular Oncology, H. Lee Moffitt Cancer Center, Tampa, Florida 33612. Electronic address: john.koomen@moffitt.org.
Cheng
Jin Q
JQ
From the Departments of Molecular Oncology, H. Lee Moffitt Cancer Center, Tampa, Florida 33612. Electronic address: jin.cheng@moffitt.org.
D019943:Amino Acid Substitution; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D019938:Cyclin D1 / Q000235:genetics; D019008:Drug Resistance, Neoplasm; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism*; D015151:Immunoblotting; D010766:Phosphorylation; D011485:Protein Binding; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012694:Serine / Q000235:genetics / Q000378:metabolism*; D013629:Tamoxifen / Q000494:pharmacology*; D015533:Transcriptional Activation; D014162:Transfection
D018931:Antineoplastic Agents, Hormonal; D047628:Estrogen Receptor alpha; D013629:Tamoxifen; D019938:Cyclin D1; D012694:Serine; D051550:I-kappa B Kinase