Sustained expression of steroid receptor coactivator SRC-2/TIF-2 is associated with better prognosis in malignant pleural mesothelioma.
BACKGROUND
Estrogen receptor beta (ERβ) overexpression by malignant pleural mesothelioma (MPM) tumor cells correlates with enhanced patient survival. ER-regulated transcription is mediated by the p160 family of steroid receptor coactivators (SRCs), and SRC isoform overexpression is associated with worse prognosis in many steroid-related malignancies. The aim of this study was to establish whether SRC isoform expression varied between individual MPM tumors with positive or negative prognostic significance.


METHODS
Immunohistochemical analysis of tumor biopsies from 89 subjects with confirmed histological diagnosis of MPM and biopsies from 3 normal control subjects was performed to detect the expression of SRC-1, SRC-2 (TIF-2), SRC-3 (AIB-1), and ERβ. Allred scores for expression of ERβ and each of the SRCs were determined, and Kaplan-Meier survival curves were calculated to correlate biomarker expression, gender, and histology type with postdiagnosis survival.


RESULTS
ERβ and all the SRCs were expressed at high levels in normal pleural mesothelium, and expression of each biomarker was reduced or lost in a subset of the MPM subjects; however, postdiagnosis survival only significantly correlated with TIF-2 expression. Low or intermediate expression of TIF-2 correlated with reduced median postdiagnosis survival (9 months) compared with those subjects whose tumors highly expressed TIF-2 (20 months) (p = 0.036, log-rank test).


CONCLUSIONS
Maintained high expression of TIF-2 in tumor cells is a positive prognostic indicator for postdiagnosis survival in patients with confirmed MPM. This is the first clinical study to correlate high TIF-2 expression with improved patient prognosis in any malignancy.
Department of Molecular Medicine, Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital, Dublin, Ireland.
Cormac J
CJ
Jennings
Anthony
A
O'Grady
Robert
R
Cummins
Bruno
B
Murer
Mazen
M
Al-Alawi
Stephen F
SF
Madden
Luciano
L
Mutti
Brian J
BJ
Harvey
Warren
W
Thomas
Elaine W
EW
Kay
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001706:Biopsy; D047629:Estrogen Receptor beta / Q000378:metabolism; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008297:Male; D008654:Mesothelioma / Q000378:metabolism* / Q000473:pathology*; D008875:Middle Aged; D056920:Nuclear Receptor Coactivator 1 / Q000378:metabolism; D051958:Nuclear Receptor Coactivator 2 / Q000378:metabolism*; D056921:Nuclear Receptor Coactivator 3 / Q000378:metabolism; D010994:Pleura / Q000473:pathology; D010997:Pleural Neoplasms / Q000378:metabolism* / Q000473:pathology*; D011379:Prognosis; D016016:Proportional Hazards Models; D012737:Sex Factors
D014408:Biomarkers, Tumor; D047629:Estrogen Receptor beta; D051958:Nuclear Receptor Coactivator 2; D056920:Nuclear Receptor Coactivator 1; D056921:Nuclear Receptor Coactivator 3