Estrogen exposure correlates with a reduced risk of colorectal cancer (CRC). Nonetheless, little is known about the mechanisms through which estrogens protect against CRC. At least some of the effects of estrogens on CRC are likely mediated via the estrogen receptor a (ERa). Although ERa is normally expressed in colonic mucosa, ERa expression is absent in colorectal tumors. These data have led to the hypothesis that ERa is a cell autonomous tumor suppressor in the intestinal epithelium. Consistent with this hypothesis, we observe that ERa deficiency significantly increases in intestinal tumor multiplicity and size in Min mice. We hypothesize that loss of ERa expression specifically within the intestinal epithelium enhances tumor development in Min mice. Alternatively, ERa mediated signaling outside the intestinal epithelium may act indirectly to modulate intestinal tumorigenesis. To distinguish between these two possibilities, we propose to selectively reintroduce ERa expression into the intestinal epithelium of ERa null mice carrying the Min mutation using an inducible expression system. Gene expression analysis and western blotting data suggest that ERa deficiency is associated with an increase in Wnt-?-catenin signaling and ? -catenin-Tcf mediated transcription in the normal intestinal epithelium. The Wnt-p-catenin signal transduction pathway is known to play a critical role in intestinal tumorigenesis by modulating cell proliferation, cell adhesion, and cell migration. To test the hypothesis that ERa deficiency alters intestinal epithelial cell proliferation, apoptosis, and migration in Min mice, we propose to quantitatively examine each of these parameters in ERa wild type and ERa null Minl+ mice. We demonstrate that ERa deficiency in Min mice is also associated with an increase in expression of the E-cadherin gene. This observation, coupled with the data indicating that Wnt-? -catenin signaling can enhance E-cadherin mediated adhesion, has led us to hypothesize that ERa deficiency is associated with an increase in E-cadherin mediated cell adhesion. To test the hypothesis that ERa deficiency enhances the formation and/or stability of E-cadherin mediated adhesion, we will examine the effect of ERa deficiency on the expression, subcellular localization, and interaction of protein components of adhesion complexes involving E-cadherin. ? ? ? ?
| Cleveland, Alicia G; Oikarinen, Seija I; Bynote, Kimberly K et al. (2009) Disruption of estrogen receptor signaling enhances intestinal neoplasia in Apc(Min/+) mice. Carcinogenesis 30:1581-90 |
