Carcinogenesis Advance Access originally published online on November 27, 2009
Carcinogenesis 2010 31(2):269-274; doi:10.1093/carcin/bgp275
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Dietary-induced ERβ upregulation counteracts intestinal neoplasia development in intact male ApcMin/+ mice
Section of Gastroenterology, Department of Emergency and Organ Transplantation
1 Department of Pathological Anatomy, University of Bari, Ospedale Policlinico, Piazza Giulio. Cesare 11, 70124 Bari, Italy
2 CM&D Pharma Limited, London, SW1W9TR, UK
* To whom correspondence should be addressed. Tel: +39 080 5593514; Fax: +39 080 5593251; Email: a.dileo{at}gastro.uniba.it
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 (ERβ) is recognized to progressively reduce its expression in adenomatous and carcinomatous tissues in humans. Moreover, ERβ deficiency enhances small intestinal tumorigenesis in rodents. In the ApcMin/+ mouse model, we evaluated intestinal polyp development and ERβ expression plus other biological parameters influencing tumor growth (epithelial cell proliferation, apoptosis and migration) following the addition of a combination of the ERβ-selective agonist silymarin (SIL) and/or lignin (LIG) to a high-fat/low-fiber diet. Forty-five ApcMin/+ 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 ERβ 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 ERβ 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 ERβ in CRC suggesting the use of the combination of SIL-LIG as a potential approach against CRC development.
Abbreviations: Apc, adenomatous polyposis coli; BrdU, bromodeoxyuridine; CC-3, cleaved caspase-3; CRC, colorectal cancer; DSI, distal small intestine; ER, estrogen receptor; ER
, estrogen receptor alpha; ERβ, estrogen receptor beta; FAP, familial adenomatous polyposis; LIG, lignin; mRNA, messenger RNA; PCR, polymerase chain reaction; SIL, silymarin; WT, wild-type
Received May 11, 2009; revised October 28, 2009; accepted October 30, 2009.
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