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Carcinogenesis Advance Access published online on December 3, 2004
Carcinogenesis, doi:10.1093/carcin/bgh346
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Oxford University Press
Received July 28, 2004
Revised November 10, 2004
Accepted November 21, 2004

MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION

Modulation of tumor formation and intestinal cell migration by estrogens in the ApcMin/+ mouse model of colorectal cancer

Sara H. Javid 1, Amy E. Moran 1, Adelaide M. Carothers 1, Mark Redston 2, and Monica M. Bertagnolli 1*

1 Department of Surgery, Brigham and Women's Hospital, Boston, MA 02115
2 Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115

* To whom correspondence should be addressed.
Monica M. Bertagnolli, E-mail: mbertagnolli{at}partners.org


  Abstract

Epidemiologic studies suggest that post-menopausal hormone replacement therapy (HRT) reduces colorectal cancer (CRC) incidence. Phytoestrogens, including the soy isoflavone, genistein, and coumestrol, are used by many women as alternatives to HRT. Previous studies showed that ovariectomy induced a 77% increase in intestinal adenoma number in the ApcMin/+ (Min/+) mouse, an animal model of adenomatous polyposis coli, or APC, -associated CRC. Replacement of estradiol (E2) in ovariectomized Min/+ mice reduced tumor number to baseline and upregulated the expression of estrogen receptor beta (ER{beta}). We hypothesized that the phytoestrogens, genistein and coumestrol, would inhibit intestinal tumorigenesis in ovariectomized Min/+ mice.

Min/+ and Apc+/+ (WT) mice were ovariectomized and assigned to either a control diet or treatment with E2, genistein, or coumestrol. Treatment of ovariectomized Min/+ (Min/+ OX) mice with genistein resulted in a non-significant reduction in tumor number. Min/+ OX mice treated with coumestrol had significantly fewer tumors than untreated Min/+ OX controls and the same number of tumors as non-ovariectomized Min/+ mice. BrdU migration assays also demonstrated that treatment with E2 or coumestrol improved enterocyte migration rate. Immunoprecipitation and immunohistochemistry analyses showed that the impaired association of adherens junction proteins, E-cadherin and {beta}-catenin, in Min/+ mice was improved by treatment with either E2 or coumestrol. Immunoblot analyses also showed that the expression of ER{beta} was elevated in enterocytes of Min/+ OX mice treated with E2 or coumestrol as compared to those of untreated Min/+ OX mice. In conclusion, both coumestrol and E2 prevented intestinal tumorigenesis and ameliorated enterocyte migration and intercellular adhesion in the ApcMin/+ mouse model of CRC.


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