Role of estrogen receptor β in colonic epithelium

Abstract

Several papers report that the colon is one of the tissues regulated by estrogen receptor (ER)β. To better understand the physiological role of ERβ in colonic tissue, we have compared morphology, proliferation, and differentiation of colonic epithelium in ERβ −/− mice and WT littermates. BrdUrd labeling revealed that the number of proliferating cells was higher in ERβ −/− mice and that the migration of labeled cells toward the luminal surface was faster in ERβ −/− mice than in WT littermates. Additionally, in the absence of ERβ, there was a decrease in apoptosis, which was measured by immunohistochemical staining of cleaved caspase-3. The state of differentiation of the colonic epithelial cells was studied by using epithelial markers. In ERβ −/− mice, there was a significant decrease in the expression of the differentiation marker cytokeratin (CK)20 and in the cellular adhesion molecules α-catenin (an adherens junction protein) and plectin (a hemidesmosomal protein). These changes were also evident by electron microscopy as abnormalities in tight junctions and in the number and shape of desmosomes in ERβ −/− mice. These findings suggest a role for ERβ in the organization and architectural maintenance of the colon. Furthermore, our results indicate that the rapidly proliferating cells of the colonic epithelium in ERβ −/− mice are lost by increased shedding and not by increased apoptosis. In this way, hyperproliferative cells that lack ERβ do not form hyperplastic lesions and do not accumulate in the superficial epithelium.

Role of estrogen receptor β in uterine stroma and epithelium: Insights from estrogen receptor β −/− mice

“…This finding is similar to what has been observed in the ventral prostate (17) and colon (18). Thus, in the ventral prostate, colon, and uterus, ER␤ seems to be essential for driving cellular differentiation.…”

“…Although ER␣ is the predominant ER in the adult rodent uterus, ER␤ mRNA has also been detected in WT and ER␣ Ϫ/Ϫ mouse uteri (11). Targeted disruption of ER␤ in mice (12) has revealed roles for ER␤ in differentiation of various epithelial and nonepithelial cell types in many tissues and organs (13)(14)(15)(16)(17)(18)(19). In the uteri of ER␤ Ϫ/Ϫ mice, there is an exaggerated responsiveness to E 2 , resulting in enlargement of the lumen, increase in volume and protein content of uterine secretion, and induction of aberrant epithelial expression of PR after E 2 injection (13).…”

Sexual dimorphism in cancer

“…ERβ function is required for normal lung and colon morphogenesis 24,25 and its activation exerts beneficial consequences in experimental models of colon 95 , glioma 96 , mesothelioma 97 , renal cell carcinoma (RCC) 98 and T cell lymphoma 99 .…”

“…It is important to note, however, that the progesterone receptor, under intense investigation in breast cancer 21 , may also be involved in cancer of non-reproductive organs, like what recently reported for lung NSCLC 22 and colon cancer 23 . a) Stem cell renewal : Specific ablation of estrogen receptor α, β and androgen receptor affects homeostasis and/or regeneration of organs unrelated to reproductive functions, such as lung 24, , colon 25 and skin [26][27][28] . Sex steroids have an impact on stem cell populations of various types.…”

Effect of ligand-activated estrogen receptor β on lymphoma growth in vitro and in vivo

“…Although estrogens via ERa stimulates proliferation in the breast, uterus and developing prostate, [6][7][8] thereby increasing the risk of tumor development and progression, estrogens via ERb inhibit proliferation and promotes differentiation of the prostate, mammary gland, colon, lung and stem cells of the bone marrow. [9][10][11][12][13] An antiproliferative effect of ERb is also suggested from experiments in ERb knockout mice, which display a myeloproliferative disease resembling human chronic myeloid leukemia with lymphoid blast crisis and prostate hyperplasia, suggesting that ERb may act as a tumor suppressor. 9,13 Furthermore, transfection of ER-negative cancer cell lines with ERb also results in reduced proliferation.…”