Tyrosine phosphorylation regulates ERβ ubiquitination, protein turnover, and inhibition of breast cancer.
Unlike estrogen receptor α (ERα) that predominantly promotes hormone-dependent breast tumor growth, ERβ exhibits antitumor effects in a variety of cancer types. We recently identified a phosphotyrosine residue in ERβ, but not ERα, that dictates ERβ transcriptional activity and antitumor function. We show here that this ER isotype-specific phosphotyrosine switch is important for regulating ERβ activity in cell proliferation, migration, and invasion. At the mechanistic level, phosphorylated ERβ, which recruits transcriptional coactivator p300, is in turn targeted by p300 for ubiquitination and proteasome-dependent protein turnover. Furthermore, ERβ-specific agonists such as S-equol enhance ERβ phosphorylation, suggesting a crosstalk between ligand- and posttranslational modification-dependent ERβ activation. Inhibition of xenograft tumor growth by S-equol is associated with reduced tumor Ki-67 expression and elevated ERβ tyrosine phosphorylation. Taken together, our data support the notion that phosphotyrosine-dependent ERβ signaling is an attractive target for anticancer treatment.
Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Collaborative Innovation Center for Cancer Medicine, Beijing, China.|Institute of Cancer Stem Cell, Cancer Center, Dalian Medical University, Liaoning, China.|Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
Bin
B
Yuan
Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Collaborative Innovation Center for Cancer Medicine, Beijing, China.
Long
L
Cheng
Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
Kshama
K
Gupta
Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
Huai-Chin
HC
Chiang
Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
Harshita B
HB
Gupta
Department of Obstetrics and Gynecology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
Gangadhara R
GR
Sareddy
Department of Epidemiology and Biostatistics, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
Degeng
D
Wang
Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
Kate
K
Lathrop
Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
Richard
R
Elledge
Department of Cellular and Structural Biology Cancer Therapy and Research Center, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
Pei
P
Wang
Center for Innovative Drug Discovery, University of Texas at San Antonio, San Antonio, TX, USA.
Stanton
S
McHardy
Department of Obstetrics and Gynecology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
Ratna
R
Vadlamudi
Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
Tyler J
TJ
Curiel
Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
Yanfen
Y
Hu
Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Collaborative Innovation Center for Cancer Medicine, Beijing, China.|Institute of Cancer Stem Cell, Cancer Center, Dalian Medical University, Liaoning, China.
Qinong
Q
Ye
Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
Rong
R
Li
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D049109:Cell Proliferation; D002470:Cell Survival; D047629:Estrogen Receptor beta / Q000378:metabolism*; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D019394:Ki-67 Antigen / Q000378:metabolism; D008024:Ligands; D061986:MCF-7 Cells; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000737:chemistry; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D014443:Tyrosine / Q000737:chemistry*; D054875:Ubiquitination; D050880:p300-CBP Transcription Factors / Q000378:metabolism
D000970:Antineoplastic Agents; C000600034:ESR2 protein, human; D047629:Estrogen Receptor beta; D019394:Ki-67 Antigen; D008024:Ligands; D019000:Phosphotyrosine; D014443:Tyrosine; D050880:p300-CBP Transcription Factors; D046988:Proteasome Endopeptidase Complex
ERβ; antitumor activity; protein turnover; tyrosine phosphorylation; ubiquitination