Gene

Cell biology

Biology

Estrogen receptor beta

Endocrinology

Estrogen

Receptor

Azoxymethane

Cancer research

Biochemistry

Computer science

Promoter

Estrogen receptor

Knockout mouse

Estrogen receptor alpha

Immunology

Chromatin immunoprecipitation

Genetics

Colitis

Inflammation

Internal medicine

Medicine

Programming language

BETA (programming language)

Carcinogenesis

Breast cancer

Cancer

Gene expression

Cancer Letters

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.

Intestinal estrogen receptor beta suppresses colon inflammation and tumorigenesis in both sexes