How estrogen receptors of the colon create a microenvironment that suppress carcinogenesis - for cancer prevention and treatment

Colorectal cancer is a leading cause of cancer mortality.

The disease exhibits distinct sex differences in incidence, tumor location, tumor characteristics, and survival, and estrogen reduces the incidence and mortality. Emerging data support that estrogen receptor beta (ERβ) mediates this effect. We have demonstrated that intestinal ERβ is protective in both sexes.

Our preliminary data show that ERβ in the tumor microenvironment reduces the number of tumor-infiltrating macrophages, stemness markers, and stabilizes circadian clock regulation, in part by modifying inflammatory NFkB signaling.

We will test our specific hypotheses using intestinal-specific knockout mice, tumor models, engineered cell lines, organotypic patient-derived cultures, and advanced technologies.

Technologies includes high-throughput hyperplex immunofluorescence COMET for spatial proteomics to characterize the immune cell landscape in situ, multiplex plasma cytokine analysis, and capture Hi-C and RIME to deduce and characterize the related molecular mechanisms.

The overarching goal is to understand the critical mechanistic background needed to develop useful strategies for chemoprevention and precision medicine, for example, co-administration of receptor-selective ligands and immune checkpoint inhibitors.

In addition, we will provide an in-depth understanding of colitis, colon carcinogenesis, peripheral circadian rhythmicity, stemness, and related sex differences.