A hypersensitive estrogen receptor-alpha mutation in premalignant breast lesions.
The best current model of breast cancer evolution suggests that most cancers arise from certain premalignant lesions. We have identified a common (34%) somatic mutation in the estrogen receptor (ER)-alpha gene in a series of 59 typical hyperplasias, a type of early premalignant breast lesion. The mutation, which affects the border of the hinge and hormone binding domains of ER-alpha, showed increased sensitivity to estrogen as compared with wild-type ER-alpha in stably transfected breast cancer cells, including markedly increased proliferation at subphysiological levels of estrogen. The mutated ER-alpha exhibits enhanced binding to the TIF-2 coactivator at low levels of hormone, which may partially explain its increased estrogen responsiveness. These data suggest that this mutation may promote or accelerate the development of cancer from premalignant breast lesions.
Fuqua
S A
SA
Breast Center, Baylor College of Medicine, Houston, Texas 77030, USA. sfuqua@bcm.tmc.edu
Wiltschke
C
C
Zhang
Q X
QX
Borg
A
A
Castles
C G
CG
Friedrichs
W E
WE
Hopp
T
T
Hilsenbeck
S
S
Mohsin
S
S
O'Connell
P
P
Allred
D C
DC
D001940:Breast / Q000473:pathology* / Q000502:physiology; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D004247:DNA / Q000032:analysis / Q000235:genetics; D004273:DNA, Neoplasm / Q000032:analysis / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000494:pharmacology; D047628:Estrogen Receptor alpha; D006801:Humans; D006965:Hyperplasia / Q000235:genetics / Q000473:pathology; D009154:Mutation; D011230:Precancerous Conditions / Q000235:genetics* / Q000473:pathology; D011960:Receptors, Estrogen / Q000187:drug effects / Q000235:genetics* / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection
D004273:DNA, Neoplasm; D047628:Estrogen Receptor alpha; D011960:Receptors, Estrogen; D004958:Estradiol; D004247:DNA