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.

Subject headings

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Cancer och onkologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Cancer and Oncology (hsv//eng)

Keyword

Breast/pathology

Breast Neoplasms/genetics

Cell Division/drug effects

DNA/analysis

DNA, Neoplasm/analysis

Dose-Response Relationship, Drug

Estradiol/pharmacology

Estrogen Receptor alpha

Humans

Hyperplasia/genetics

Mutation

Precancerous Conditions/genetics

Receptors, Estrogen/drug effects

Reverse Transcriptase Polymerase Chain Reaction

Transfection

Publication and Content Type

art (subject category)

ref (subject category)