Disruption of estrogen receptor signaling enhances intestinal neoplasia in Apc(Min/+) mice.
Estrogen receptors (ERs) [ERalpha (Esr1) and ERbeta (Esr2)] are expressed in the human colon, but during the multistep process of colorectal carcinogenesis, expression of both ERalpha and ERbeta is lost, suggesting that loss of ER function might promote colorectal carcinogenesis. Through crosses between an ERalpha knockout and Apc(Min) mouse strains, we demonstrate that ERalpha deficiency is associated with a significant increase in intestinal tumor multiplicity, size and burden in Apc(Min/+) mice. Within the normal intestinal epithelium of Apc(Min/+) mice, ERalpha deficiency is associated with an accumulation of nuclear beta-catenin, an indicator of activation of the Wnt-beta-catenin-signaling pathway, which is known to play a critical role in intestinal cancers. Consistent with the hypothesis that ERalpha deficiency is associated with activation of Wnt-beta-catenin signaling, ERalpha deficiency in the intestinal epithelium of Apc(Min/+) mice also correlated with increased expression of Wnt-beta-catenin target genes. Through crosses between an ERbeta knockout and Apc(Min) mouse strains, we observed some evidence that ERbeta deficiency is associated with an increased incidence of colon tumors in Apc(Min/+) mice. This effect of ERbeta deficiency does not involve modulation of Wnt-beta-catenin signaling. Our studies suggest that ERalpha and ERbeta signaling modulate colorectal carcinogenesis, and ERalpha does so, at least in part, by regulating the activity of the Wnt-beta-catenin pathway.
Cleveland
Alicia G
AG
Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE 68198, USA.
Oikarinen
Seija I
SI
Bynoté
Kimberly K
KK
Marttinen
Maija
M
Rafter
Joseph J
JJ
Gustafsson
Jan-Ake
JA
Roy
Shyamal K
SK
Pitot
Henry C
HC
Korach
Kenneth S
KS
Lubahn
Dennis B
DB
Mutanen
Marja
M
Gould
Karen A
KA
D000818:Animals; D015820:Cadherins / Q000032:analysis; D003106:Colon / Q000737:chemistry; D019938:Cyclin D1 / Q000032:analysis; D004958:Estradiol / Q000097:blood; D047628:Estrogen Receptor alpha / Q000172:deficiency* / Q000502:physiology; D047629:Estrogen Receptor beta / Q000172:deficiency* / Q000502:physiology; D005260:Female; D017491:Genes, APC; D007414:Intestinal Neoplasms / Q000209:etiology* / Q000235:genetics; D008297:Male; D051379:Mice; D010053:Ovary / Q000473:pathology; D015398:Signal Transduction / Q000502:physiology*; D051153:Wnt Proteins / Q000502:physiology; D051176:beta Catenin / Q000032:analysis / Q000502:physiology
D015820:Cadherins; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D051153:Wnt Proteins; D051176:beta Catenin; D019938:Cyclin D1; D004958:Estradiol