# RET is a sex-biased regulator of intestinal tumorigenesis

## TL;DR

The RET gene influences intestinal tumor growth differently in males and females, with the effect mediated by gut microbes.

## Contribution

RET is identified as a sex-biased regulator of tumorigenesis influenced by the microbiome in an Apc-deficient CRC model.

## Key findings

- ApcMin/+Ret+/− females had significantly more tumors than males, a sex bias not seen in ApcMin/+ mice.
- Antibiotics reduced tumor burden and reversed the sex bias, while microbiome reconstitution restored it.
- RET and TLR4 expression were correlated in female but not male tumor samples.

## Abstract

Ret is implicated in colorectal cancer (CRC) as both a proto-oncogene and a tumor suppressor. We asked whether RET signaling regulates tumorigenesis in an Apc-deficient preclinical model of CRC. We observed a sex-biased phenotype: ApcMin/+Ret+/− females had significantly greater tumor burden than ApcMin/+Ret+/− males, a phenomenon not seen in ApcMin/+ 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 Apc tumor suppressor gene. Ret and Tlr4 expression were significantly correlated in tumor samples from female but not male ApcMin/+Ret+/− mice. Antibiotics resulted in reduction of tumor burden, inverting the sex-biased phenotype such that microbiota-depleted ApcMin/+Ret+/− 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.