ERß expression in normal, adenomatous and carcinomatous tissues of patients with familial adenomatous polyposis.

OBJECTIVES: The APC gene mutation triggers familial adenomatous polyposis (FAP) and approximately 80% of sporadic colorectal cancers. FAP summarizes the natural history of colorectal cancer because low- and high-grade dysplastic lesions and adenocarcinoma are simultaneously present in the same patients free from individual and environmental variability factors. Estrogen receptor beta (ERß) has recently been suggested as the most likely mediator of estrogen-related anti-carcinogenic effects in Apc(Min-/+) mice and humans. In this study we assessed the ERß expression in the intestinal mucosa of FAP patients to verify its possible involvement in tumor progression in colorectal cancer. MATERIAL AND METHODS: ERß and ERα expression, cell proliferation (Ki-67) and apoptosis (TUNEL), were evaluated on archival biopsy material from six patients with FAP who underwent colectomy. RESULTS: A progressive significant decrease of ERß expression was observed in the different stages of the disease as compared to normal mucosa (p < 0.001). Interestingly, a decreased ERß expression was directly correlated with apoptosis (r = 0.76, p < 0.001), and inversely correlated with cell proliferation (r = 0.54, p < 0.05). CONCLUSIONS: ERß expression is related to the severity of the disease, supporting the role of ERß as a relevant biomarker of tumor progression and possible chemopreventive target in patients at risk of colonic neoplasia.

Dietary-induced ERbeta upregulation counteracts intestinal neoplasia development in intact male ApcMin/+ mice.

Most sporadic colorectal cancers (CRCs) develop through the adenoma-carcinoma sequence pathway and are initiated by adenomatous polyposis coli (APC) gene mutations. Estrogen receptor beta (ERbeta) is recognized to progressively reduce its expression in adenomatous and carcinomatous tissues in humans. Moreover, ERbeta deficiency enhances small intestinal tumorigenesis in rodents. In the Apc(Min/+) mouse model, we evaluated intestinal polyp development and ERbeta expression plus other biological parameters influencing tumor growth (epithelial cell proliferation, apoptosis and migration) following the addition of a combination of the ERbeta-selective agonist silymarin (SIL) and/or lignin (LIG) to a high-fat/low-fiber diet. Forty-five Apc(Min/+) mice were divided in four groups: animals fed on the tumorigenic high-fat/low-fiber diet, the tumorigenic diet supplemented with SIL (0.02%) or purified LIG (6.24%) or SIL (0.005%) + LIG (6.24%). In these animals, we assessed polyp number and volume and their degree of dysplasia together with ERbeta messenger RNA (mRNA) and protein levels and epithelial cell proliferation, migration and apoptosis. The latter group of parameters was evaluated in normal and adenomatous mucosa and the results compared with those found in wild-type (WT) mice fed on the control diet. The addition of SIL or LIG to the diet and even more the specific combination of the two significantly counteracted intestinal tumorigenesis and increased ERbeta mRNA and protein levels. Cell proliferation and apoptosis were rebalanced and cell migration accelerated, restoring values similar to those observed in WT animals. Our results further support a protective effect of ERbeta in CRC suggesting the use of the combination of SIL-LIG as a potential approach against CRC development.