Src promotes estrogen-dependent estrogen receptor alpha proteolysis in human breast cancer.
Estrogen drives both transcriptional activation and proteolysis of estrogen receptor alpha (ER alpha; encoded by ESR1). Here we observed variable and overlapping ESR1 mRNA levels in 200 ER alpha-negative and 50 ER alpha-positive primary breast cancers examined, which suggests important posttranscriptional ER alpha regulation. Our results indicate that Src cooperates with estrogen to activate ER alpha proteolysis. Inducible Src stimulated ligand-activated ER alpha transcriptional activity and reduced ER alpha t(1/2). Src and ER alpha levels were inversely correlated in primary breast cancers. ER alpha-negative primary breast cancers and cell lines showed increased Src levels and/or activity compared with ER alpha-positive cancers and cells. ER alpha t(1/2) was reduced in ER alpha-negative cell lines. In both ER alpha-positive and -negative cell lines, both proteasome and Src inhibitors increased ER alpha levels. Src inhibition impaired ligand-activated ER alpha ubiquitylation and increased ER alpha levels. Src siRNA impaired ligand-activated ER alpha loss in BT-20 cells. Pretreatment with Src increased ER alpha ubiquitylation and degradation in vitro. These findings provide what we believe to be a novel link between Src activation and ER alpha proteolysis and support a model whereby crosstalk between liganded ER alpha and Src drives ER alpha transcriptional activity and targets ER alpha for ubiquitin-dependent proteolysis. Oncogenic Src activation may promote not only proliferation, but also estrogen-activated ER alpha loss in a subset of ER alpha-negative breast cancers, altering prognosis and response to therapy.
Chu
Isabel
I
Braman Family Breast Cancer Institute and Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida 33136, USA.
Arnaout
Angel
A
Loiseau
Sophie
S
Sun
Jun
J
Seth
Arun
A
McMahon
Chris
C
Chun
Kathy
K
Hennessy
Bryan
B
Mills
Gordon B
GB
Nawaz
Zafar
Z
Slingerland
Joyce M
JM
D001943:Breast Neoplasms / Q000175:diagnosis / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000187:drug effects; D047628:Estrogen Receptor alpha / Q000096:biosynthesis*; D004967:Estrogens / Q000378:metabolism / Q000494:pharmacology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D009363:Neoplasm Proteins / Q000096:biosynthesis*; D011379:Prognosis; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D012333:RNA, Messenger / Q000096:biosynthesis; D012334:RNA, Neoplasm / Q000096:biosynthesis; D034741:RNA, Small Interfering / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects; D025801:Ubiquitin / Q000378:metabolism; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
D047628:Estrogen Receptor alpha; D004967:Estrogens; D009363:Neoplasm Proteins; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D034741:RNA, Small Interfering; D025801:Ubiquitin; D019061:src-Family Kinases; D046988:Proteasome Endopeptidase Complex