̽����ѡ

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.

Colon and rectal cancer is the third most common cause of cancer death for both men and women in Sweden. There is a great need to develop better prevention, treatments and prognostic biomarkers. The female sex hormone estrogen is protective, but estrogen has side effects that make it unsuitable as a contraceptive. We have shown that a special estrogen receptor, ERbeta, in the intestinal epithelial cells is the protein that mediates the protective effect of estrogen. Our hypothesis is that activation of the ERbeta receptor can be used for a safe preventive treatment with few or no side effects. Our new results show that the receptor has a cancer-protective effect in both sexes. In addition, we see a strong anti-inflammatory effect in the intestine and signs that the receptor also seems to be able to regulate the biological circadian rhythm of the intestine. Both inflammation and the intestinal circadian rhythm are associated with cancer development. A partial hypothesis is that the intestinal microflora is also affected by ERbeta activation. Our aim here is to explore exactly how this works and clarify how the receptor protects against the onset of cancer. Our goal is to be able to develop a new safe preventive treatment that protects both men and women. Such treatment may be suitable for people in risk groups who have hereditary syndromes that increase the risk of rectal and colon cancer, as well as for the elderly.