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Estrogen Receptors and ß Are Inhibitory Modifiers of Apc-Dependent Tumorigenesis in the Proximal Colon of Min/+ Mice

Departments of ¹ Surgery and ² Pathology, Brigham and Women's Hospital, Boston, Massachusetts

Requests for reprints: Monica M. Bertagnolli, Department of Surgery, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115. Phone: 617-732-8991; Fax: 617-582-6177; E-mail: mbertagnolli{at}partners.org.

Estrogen replacement therapy in postmenopausal women is associated with a reduction in colorectal cancer risk, potentially via interactions between 17ß-estradiol (E₂) and the estrogen receptors (ER) and ß. To study the role of E₂ in intestinal tumor inhibition, we separately crossed C57BL/6J-Min/+ (Min/+) mice with Er^+/– and Erß^+/– 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^+/–Min/+ mice, suggesting that ER 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 E₂-treated OvxMin/+ mice (OvxMin/+ +E₂), 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 and ERß was regionally compartmentalized along the colonic crypt axis, suggesting functional antagonism. Our results indicate that ER and ERß are inhibitory modifiers of Apc-dependent colon tumorigenesis. As a result, loss of E₂ and ER signaling in postmenopausal women may contribute to colorectal cancer development. [Cancer Res 2007;67(5):2366–72]

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