The prognostic significance of steroid receptor co-regulators in breast cancer: co-repressor NCOR2/SMRT is an independent indicator of poor outcome.
BACKGROUND
Advances in understanding the molecular basis of breast cancer has necessitated a definition of improved indicators of prognosis that are central to the underlying cancer biology and that reflect the heterogeneous nature of the disease. This study investigates the pattern of expression of the steroid receptor co-regulators NCOA1/SRC1, NCOA3/RAC3, NCOR2/SMRT, and CBP/p300 in breast cancer. The aims were to identify whether their expression was related to patient outcome, their relationships to known prognostic factors and to provide a basis for further research into the mechanistic significance of such associations.


METHODS
The protein levels of steroid receptor co-regulators were assessed by immunohistochemistry in a large well-characterised series of breast carcinomas prepared as tissue microarrays. Relationships between these targets, other clinicopathological variables and patients' outcome were examined.


RESULTS
NCOR2/SMRT was an independent prognostic indicator of overall patient survival (OS) and disease free interval (DFI) and was significantly correlated with distant metastases and local recurrence whereas tumours expressing NCOA1/SRC1 had a significantly longer OS and DFI. There were also significant correlations between co-regulator expression of NCOA1/SRC1, CBP/p300 and NCOA3/RAC3, which were associated with lower tumour grade. NCOA1/SRC1 was also correlated with smaller tumour size. Furthermore, the co-activators had a significant association with steroid receptors, particularly ERalpha.


CONCLUSIONS
NCOR2/SMRT is associated with poor patient outcome, independent of other prognostic factors. In contrast, steroid receptor co-activator expression is generally associated with a good prognosis. Further investigations are needed to establish the mechanisms of these links between the steroid receptor co-regulator system and patient outcome.
Green
Andrew R
AR
Division of Pathology, School of Molecular Medical Sciences, Nottingham University Hospitals NHS and University of Nottingham, Nottingham, UK. andrew.green@nottingham.ac.uk
Burney
Claire
C
Granger
Christopher J
CJ
Paish
E Claire
EC
El-Sheikh
Somaia
S
Rakha
Emad A
EA
Powe
Desmond G
DG
Macmillan
R Douglas
RD
Ellis
Ian O
IO
Stylianou
Eleni
E
D014408:Biomarkers, Tumor / Q000032:analysis*; D001943:Breast Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D004268:DNA-Binding Proteins / Q000096:biosynthesis*; D005260:Female; D051548:Histone Acetyltransferases / Q000096:biosynthesis; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D056985:Nuclear Receptor Co-Repressor 2; D056920:Nuclear Receptor Coactivator 1; D056921:Nuclear Receptor Coactivator 3; D011379:Prognosis; D012097:Repressor Proteins / Q000096:biosynthesis*; D046888:Tissue Array Analysis; D015534:Trans-Activators / Q000096:biosynthesis; D014157:Transcription Factors / Q000096:biosynthesis; D016896:Treatment Outcome; D050880:p300-CBP Transcription Factors / Q000096:biosynthesis
D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; C539130:NCOR2 protein, human; D056985:Nuclear Receptor Co-Repressor 2; D012097:Repressor Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D051548:Histone Acetyltransferases; C538859:NCOA1 protein, human; C538866:NCOA3 protein, human; D056920:Nuclear Receptor Coactivator 1; D056921:Nuclear Receptor Coactivator 3; D050880:p300-CBP Transcription Factors