ERbeta isoform expression in colorectal carcinoma: an in vivo and in vitro study of clinicopathological and molecular correlates.
Colorectal carcinoma shows several sex-related differences with regard to incidence, response to chemotherapy and microsatellite instability. These differences may relate to differential expression of ERbeta1 (wild-type) as well as the truncated ERbeta2 and ERbeta5 splice variant isoforms, which have recently been detected in normal and malignant colorectal epithelium. This hypothesis was tested through the study of ERbeta isoform protein and/or mRNA expression amongst 91 primary colorectal carcinoma cases and 20 colorectal carcinoma cell lines. Study of the latter showed an absolute correlation between mRNA and protein expressions for ERbeta1 and ERbeta2. ERbeta1 and ERbeta2 protein expression was lost in 22% and 49%, respectively, of the primary colorectal carcinomas. By contrast, ERbeta5 expression was found in all primary colorectal carcinomas and all colorectal carcinoma cell lines studied. Lower ERbeta1 protein expression was associated with poorer differentiation, higher pT stage and absence of microsatellite instability. Higher ERbeta2 protein expression was associated with right-sided location and presence of lymph node metastases. Protein expression of ERbeta1 correlated positively with expression of the oestrogen-responsive protein trefoil factor 1 (TFF1). There was no correlation between ERbeta protein isoform expression and response to 5-fluorouracil therapy, tumour proliferation, or thymidylate synthase expression. These data suggest that ERbeta1 and/or ERbeta2 isoform expression may have prognostic value and may explain sex-related differences in microsatellite instability and colorectal carcinoma. The opposing associations shown by ERbeta1 and/or ERbeta2 in relation to colorectal carcinoma are in keeping with differential activities shown by the two isoforms.
Wong
Newton A C S
NA
Cancer Research UK Cancer and Immunogenetics Laboratory, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, UK. nacs.wong@bristol.ac.uk
Malcomson
Roger D G
RD
Jodrell
Duncan I
DI
Groome
Nigel P
NP
Harrison
David J
DJ
Saunders
Philippa T K
PT
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D015331:Cohort Studies; D003106:Colon / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D047629:Estrogen Receptor beta / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D042822:Genomic Instability; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000378:metabolism; D011379:Prognosis; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics; D012007:Rectum / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012737:Sex Factors; D014407:Tumor Cells, Cultured
D014408:Biomarkers, Tumor; D047629:Estrogen Receptor beta; D009363:Neoplasm Proteins; D020033:Protein Isoforms; D012333:RNA, Messenger; D012334:RNA, Neoplasm