Estrogen receptors alpha and beta are inhibitory modifiers of Apc-dependent tumorigenesis in the proximal colon of Min/+ mice.
Estrogen replacement therapy in postmenopausal women is associated with a reduction in colorectal cancer risk, potentially via interactions between 17beta-estradiol (E(2)) and the estrogen receptors (ER) alpha and beta. To study the role of E(2) in intestinal tumor inhibition, we separately crossed C57BL/6J-Min/+ (Min/+) mice with Eralpha(+/-) and Erbeta(+/-) mice to generate ER-deficient Min/+ progeny. We found an increased incidence of visible colon tumors and dysplastic microadenomas in ER-deficient Min/+ relative to Er(+/+)Min/+ controls. Small intestinal tumor numbers were unaffected. Invasive carcinomas were found only in Eralpha(+/-)Min/+ mice, suggesting that ERalpha plays additional non-cell autonomous roles that limit tumor progression. Histologic analyses of ER-deficient Min/+ colons, as well as colons from ovariectomized Min/+ mice (OvxMin/+) and E(2)-treated OvxMin/+ mice (OvxMin/+ +E(2)), revealed significant differences in crypt architecture, enterocyte proliferation, and goblet cell differentiation relative to Min/+ and Er(+/+)Apc(+/+) (wild-type) controls. The expression of ERalpha and ERbeta was regionally compartmentalized along the colonic crypt axis, suggesting functional antagonism. Our results indicate that ERalpha and ERbeta are inhibitory modifiers of Apc-dependent colon tumorigenesis. As a result, loss of E(2) and ER signaling in postmenopausal women may contribute to colorectal cancer development.
Cho
Nancy L
NL
Departments of Surgery and Pathology, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA.
Javid
Sara H
SH
Carothers
Adelaide M
AM
Redston
Mark
M
Bertagnolli
Monica M
MM
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D003110:Colonic Neoplasms / Q000235:genetics / Q000473:pathology*; D020895:Enterocytes / Q000166:cytology / Q000187:drug effects; D047628:Estrogen Receptor alpha / Q000502:physiology*; D047629:Estrogen Receptor beta / Q000502:physiology*; D004967:Estrogens / Q000494:pharmacology; D005260:Female; D017491:Genes, APC; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008954:Models, Biological
D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004967:Estrogens