Coassociation of estrogen receptor and p160 proteins predicts resistance to endocrine treatment; SRC-1 is an independent predictor of breast cancer recurrence.
OBJECTIVE
This study investigates the role of the p160 coactivators AIB1 and SRC-1 independently, and their interactions with the estrogen receptor, in the development of resistance to endocrine treatments.


METHODS
The expression of the p160s and the estrogen receptor, and their interactions, was analyzed by immunohistochemistry and quantitative coassociation immunofluorescent microscopy, using cell lines, primary breast tumor cell cultures, and a tissue microarray with breast cancer samples from 560 patients.


RESULTS
Coassociation of the p160s and estrogen receptor alpha was increased in the LY2 endocrine-resistant cell line following treatment with tamoxifen in comparison with endocrine-sensitive MCF-7 cells. In primary cultures, there was an increase in association of the coactivators with estrogen receptor alpha following estrogen treatment but dissociation was evident with tamoxifen. Immunohistochemical staining of the tissue microarray revealed that SRC-1 was a strong predictor of reduced disease-free survival (DFS), both in patients receiving adjuvant tamoxifen treatment and untreated patients (P < 0.0001 and P = 0.0111, respectively). SRC-1 was assigned a hazard ratio of 2.12 using a Cox proportional hazards model. Endocrine-treated patients who coexpressed AIB1 with human epidermal growth factor receptor 2 had a significantly shorter DFS compared with all other patients (P = 0.03). Quantitative coassociation analysis in the patient tissue microarray revealed significantly stronger colocalization of AIB1 and SRC-1 with estrogen receptor alpha in patients who have relapsed in comparison with those patients who did not recur (P = 0.026 and P = 0.00001, respectively).


CONCLUSIONS
SRC-1 is a strong independent predictor of reduced DFS, whereas the interactions of the p160 proteins with estrogen receptor alpha can predict the response of patients to endocrine treatment.
Redmond
Aisling M
AM
Endocrine Oncology Research Group, Department of Surgery, Royal College of Surgeons in Ireland, Dublin, Ireland.
Bane
Fiona T
FT
Stafford
Anthony T
AT
McIlroy
Marie
M
Dillon
Mary F
MF
Crotty
Thomas B
TB
Hill
Arnold D
AD
Young
Leonie S
LS
D001943:Breast Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000401:mortality; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm; D047628:Estrogen Receptor alpha / Q000032:analysis / Q000502:physiology*; D005260:Female; D051548:Histone Acetyltransferases / Q000032:analysis / Q000502:physiology*; D006801:Humans; D009364:Neoplasm Recurrence, Local / Q000209:etiology*; D009687:Nuclear Proteins / Q000032:analysis / Q000502:physiology*; D056920:Nuclear Receptor Coactivator 1; D056921:Nuclear Receptor Coactivator 3; D029543:Nucleocytoplasmic Transport Proteins / Q000032:analysis / Q000502:physiology*; D011379:Prognosis; D016601:RNA-Binding Proteins; D013629:Tamoxifen / Q000627:therapeutic use*; D046888:Tissue Array Analysis; D015534:Trans-Activators / Q000032:analysis / Q000502:physiology; D014157:Transcription Factors / Q000032:analysis / Q000502:physiology*
D004268:DNA-Binding Proteins; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; C491719:MYBBP1A protein, human; D009687:Nuclear Proteins; D029543:Nucleocytoplasmic Transport Proteins; D016601:RNA-Binding Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D013629:Tamoxifen; D051548:Histone Acetyltransferases; C538859:NCOA1 protein, human; C538866:NCOA3 protein, human; D056920:Nuclear Receptor Coactivator 1; D056921:Nuclear Receptor Coactivator 3