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Purpose: Estrogen receptor beta (ER beta) is abundantly expressed in colorectal tissue, but its role in colorectal carcinogenesis remains elusive. Estrogen receptor coregulators, amplified in breast cancer 1 (AIB1) and transcription intermediary factor 2 (TIF2), have been well-characterized, but their expression in colorectal carcinomas has not been investigated., Materials and Methods: Estrogen receptor alpha (ER alpha), ER beta, AIB1, and TIF2 protein expression were evaluated by immunohistochemistry in colorectal normal mucosa, adenomas, and adenocarcinomas from 110 patients with colorectal cancer., Results: ER alpha expression was rare in colorectal tissue and its expression does not appear to be associated with colorectal carcinogenesis. ER beta, AIB1, and TIF2 were detected in the nucleus of epithelial, endothelial, inflammatory, smooth muscle cells, and myofibroblasts. The expression of the three proteins was significantly increased in epithelial cells of carcinomas compared to normal mucosa. In carcinomas, a significant correlation between the levels of expression of AIB1 and TIF2 was noted. Although AIB1 overexpression was associated with local tumor invasion, it was also found to correlate independently with prolonged overall survival., Conclusions: ER beta, AIB1, and TIF2 appear to be involved in colorectal tumorigenesis and might have prognostic significance.

Epidemiological and molecular data suggest the involvement of estrogen signaling in colorectal tissue, mediated mainly through estrogen receptor beta (ERbeta). Estrogens may mediate their effects in epithelial cells indirectly by acting on stromal cells. Expression of ERalpha, ERbeta1, and the ER coregulators, amplified in breast cancer-1 (AIB-1) and transcriptional intermediary factor 2 (TIF-2), was evaluated in myofibroblasts of 107 colorectal carcinomas, 77 paired samples of normal mucosa, and 29 adenomas by immunohistochemistry. Double immunostaining with a-SMA was used to identify the myofibroblasts of normal tissue, adenomas, and cancer microenvironment. ERalpha was not expressed in stromal cells. Nuclear expression of ERbeta1, AIB-1, and TIF-2 in myofibroblasts gradually increased from normal mucosa, through adenomas, to carcinomas. Cytoplasmic ERbeta1 and TIF-2 expression was enhanced in carcinomas compared to normal mucosa and adenomas. Enhanced nuclear and cytoplasmic ERbeta1 expression and elevated nuclear AIB-1 expression were more frequently noted in myofibroblasts of carcinomas of advanced stage. ERbeta1 expression in cancer-associated myofibroblasts correlated to AIB-1 and TIF-2 expression. None of the markers correlated with patients' prognosis. Our findings imply that ERbeta1-dependent (genomic and non-genomic) and ER-coregulator-dependent (AIB-1, TIF-2) signal transductions in myofibroblasts may be involved in the initiation and progression of colorectal carcinomas.

Background: Estrogen receptor beta (ERbeta) is abundantly expressed in colorectal tissue, but its role in colorectal carcinogenesis remains elusive. ER novel co-regulator, proline-, glutamic acid- and leucine-rich protein 1 (PELP1/MNAR) has been characterized, but its expression in colorectal carcinomas has not been investigated., Methods: ERalpha, ERbeta and PELP1/MNAR protein expression were evaluated by immunohistochemistry in colorectal normal mucosa, adenomas and adenocarcinomas from 113 patients with colorectal cancer., Results: ERalpha expression is extremely rare in colorectal tissue and its expression does not appear to be associated with colorectal carcinogenesis. ERbeta and PELP1/MNAR were detected in the nucleus of epithelial, endothelial, inflammatory, smooth muscle cells and myofibroblasts. When intensity of staining was taken into account, the expression of both proteins was significantly increased in epithelial cells of carcinomas compared to normal mucosa. ERbeta expression in epithelial cells was correlated with decreased disease progression - free survival. PELP1/MNAR overexpression in epithelial cells was found to be an independent favorable prognostic factor. Additionally, the expression of both proteins was significantly increased in stromal myofibroblasts of carcinomas compared to adenomas and normal mucosa., Conclusion: ERbeta and PELP1/MNAR appear to be involved in colorectal tumorigenesis and might have prognostic significance.

Proline-, glutamic acid-, and leukine-rich protein (PELP1) is a novel co-regulatory protein that modulates genomic and non genomic actions of estrogen receptors. Nuclear receptor co-repressor (NCoR) represses estrogen-receptor-dependent transcription. PELP1 and NCoR expression was evaluated in tissue sections from 107 formalin-fixed, paraffin-embedded colectomy specimens. Normal mucosa and adenomas were also evaluated in 77 and 29 cases, respectively. PELP1 was expressed in a dot-like pattern in the nuclei of epithelial and stromal cells. Statistical analysis revealed an increase in PELP1 expression in myofibroblasts from normal mucosa through adenomas to carcinomas. NCoR was expressed in the nuclei and the cytoplasm of epithelial cells. Nuclear expression was more common in normal mucosa, whereas cytoplasmic expression was higher in malignant epithelial cells. Additionally, NCoR was expressed in the cytoplasm of cancer-associated myofibroblasts, but was rarely noted in myofibroblasts of normal mucosa or adenomas. Cytoplasmic expression of NCoR in epithelial cells correlated with better disease-free and overall survival on univariate analysis and was an independent prognostic marker for disease-free survival on multivariate analysis. These findings suggest that deregulation of co-regulators expression in both epithelial cells and myofibroblasts may contribute to the initiation and progression of colorectal carcinoma.