RET is a sex-biased regulator of intestinal tumorigenesis.

is implicated in colorectal cancer (CRC) as both a proto-oncogene and a tumor suppressor. We asked whether RET signaling regulates tumorigenesis in an -deficient preclinical model of CRC. We observed a sex-biased phenotype: +/- females had significantly greater tumor burden than Ret+/- males, a phenomenon not seen in mice, which had equal distributions by sex. Dysfunctional RET signaling was associated with gene expression changes in diverse tumor signaling pathways in tumors and normal-appearing colon. Sex-biased gene expression differences mirroring tumor phenotypes were seen in 26 genes, including the tumor suppressor gene. and expression were significantly correlated in tumor samples from female but not male +/- mice. Antibiotics resulted in reduction of tumor burden, inverting the sex-biased phenotype such that microbiota-depleted +/- males had significantly more tumors than female littermates. Reconstitution of the microbiome rescued the sex-biased phenotype. Our findings suggest that RET represents a sexually dimorphic microbiome-mediated "switch" for regulation of tumorigenesis.