Estrogen receptors α and β 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 17 beta-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 Er alpha(+/-) and Er beta(+/-) 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 Er alpha(+/-)Min/+ mice, suggesting that ER alpha plays additional non-cell autonomous roles that limit tumor progression. Histologic analyses of ERdeficient 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 ER alpha and ER beta was regionally compartmentalized along the colonic crypt axis, suggesting functional antagonism. Our results indicate that ER alpha and ER beta 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.