Abstract
Estrogen hormones protect against colorectal cancer (CRC) and a preventative role of estrogen receptor beta (ERβ) on CRC has been supported using full knockout animals. However, it is unclear through which cells or organ ERβ mediates this effect. To investigate the functional role of intestinal ERβ during colitis-associated CRC we used intestine-specific ERβ knockout mice treated with azoxymethane and dextran sodium sulfate, followed by ex vivo organoid culture to corroborate intrinsic effects. We explored genome-wide impact on TNFα signaling using human CRC cell lines and chromatin immunoprecipitation assay to mechanistically characterize the regulation of ERβ. Increased tumor formation in males and tumor size in females was noted upon intestine-specific ERβ knockout, accompanied by enhanced local expression of TNFα, deregulation of key NFκB targets, and increased colon ulceration. Unexpectedly, we noted especially strong effects in males. We corroborated that intestinal ERβ protects against TNFα-induced damage intrinsically, and characterized an underlying genome-wide signaling mechanism in CRC cell lines whereby ERβ binds to cis-regulatory chromatin areas of key NFκB regulators. Our results support a protective role of intestinal ERβ against colitis-associated CRC, proposing new therapeutic strategies.
Highlights
Chronic inflammation is one of the hallmarks of colorectal cancer (CRC) promotion and correlates with poor prognosis [1,2,3]
We note that were used as controls (WT) males had a significantly more severe response compared to females, in terms of disease activity index (DAI) after the first dextran sodium sulfate (DSS) cycle (Fig. 2A)
Our objective in this study was to determine whether intestinal epithelial ERβ is responsible for the CRC-protective effects of estrogen and to explore this mechanism
Summary
Chronic inflammation is one of the hallmarks of colorectal cancer (CRC) promotion and correlates with poor prognosis [1,2,3]. Development of a preventive therapy with less adverse effects could significantly reduce CRC incidence. Studies have indicated CRC-preventive effect of the estrogen recep tor (ER)-β, which is expressed at low levels in normal intestinal epithelial cells and declines during CRC progression [16]. Whether or how intestinal epithelia ERβ modulates CRC development has not been investigated Understanding this mechanism is critical since selective activation of ERβ could be an ideal approach for therapeutic prevention of CRC. We show that male mice are especially sensitive to a lack of ERβ in terms of inflammatory signaling and tumor number and our results support a plausible mech anism in which the protective effect of ERβ is mediated by inhibition of the inflammatory and carcinogenic effects by TNFα/NFκB signaling
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