Journal of Genetic Syndromes & Gene Therapy
Open Access

Abstract

Estrogen Receptor beta in Colorectal Cancer Prevention: Do we have Conclusive Proof?

Michele Barone and Alfredo Di Leo

Familial Adenomatous Polyposis (FAP) and Lynch syndrome are hereditary conditions that lead to Colorectal Cancer (CRC). FAP represents the ideal model for studying colorectal carcinogenesis since, in the same subject; ?normal? mucosa coexists with low and high-grade dysplastic lesions as well as adenocarcinoma, offering the opportunity to compare different parameters in the various stages of the carcinogenetic process, free from individual variations. Epidemiological studies on women in pre-or postmenopausal age assuming oral contraceptive or hormone replacement therapy, respectively, strongly suggest a protective role of estrogens on CRC and colonic adenomatous polyps. Such findings have been confirmed by studying the behavior of the two high affinity Estrogen Receptors (ERs), estrogen receptors alpha (ER-?) and estrogen receptors beta (ER-?), both in humans with sporadic CRC, FAP and sporadic polyps. ERs reduction has also been associated to microsatellite instability, a DNA mutation encountered in Lynch syndrome and in 15-25% of sporadic CRC. ER-?, abundantly expressed in the normal colon, progressively decreases in adenomas and CRC in relation to the disease aggressiveness. A similar behavior is encountered in FAP, where ER-? levels and ER-?/ER-? ratio progressively decrease in pre-neoplastic and neoplastic tissues. Finally, ER-? deficiency enhances intestinal tumorigenesis in ApcMin/+ mice, an animal model that represents the equivalent of human FAP. ER-? would act by promoting apoptosis and inhibiting the stimulatory effect of ER-? on proliferation. Recently, the use of selective ER-? agonists, such as phytoestrogens, has been suggested in primary CRC prevention. These natural compounds would represent an ideal therapeutic approach, since their use is not associated to the classic side effects encountered with either estrogens (active on both ? and ? estrogen receptors) or cyclooxygenase-2 (COX2) inhibitors. Moreover, they could be indifferently used in men and women since estrogen sexual activity is related to ER-? pathway.