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Estrogen Receptor ß Inhibits Angiogenesis and Growth of T47D Breast Cancer Xenografts

¹ Center for Biotechnology and ² Division of Medical Nutrition, Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden

Requests for reprints: Johan Hartman, Center for Biotechnology, Department of Biosciences and Nutrition, Karolinska Institutet, Novum, S-141 57 Huddinge, Sweden. Phone: 46-86089150; Fax: 46-87745538; E-mail: johan.hartman{at}biosci.ki.se.

Estrogens, which are stimulators of growth of both the normal breast and malignant breast, mediate their effects through two estrogen receptors (ER), namely ER and ERß. ER mediates the proliferative effect of estrogen in breast cancer cells, whereas ERß seems to be antiproliferative. We engineered ER-positive T47D breast cancer cells to express ERß in a Tet-Off–regulated manner. These cells were then injected orthotopically into severe combined immunodeficient mice, and the growth of the resulting tumors was compared with tumors resulting from injecting the parental T47D cells that do not express ERß. The presence of ERß resulted in a reduction in tumor growth. Comparison of the ERß-expressing and non-ERß–expressing tumors revealed that the expression of ERß caused a reduction in the number of intratumoral blood vessels and a decrease in expression of the proangiogenic factors vascular endothelial growth factor (VEGF) and platelet-derived growth factor ß (PDGFß). In cell culture, with the Tet-Off–regulated ERß-expressing cells, expression of ERß decreased expression of VEGF and PDGFß mRNA under normoxic as well as hypoxic conditions and reduced secreted VEGF and PDGFß proteins in cell culture medium. Transient transfection assays with 1,026 bp VEGF and 1,006 bp PDGFß promoter constructs revealed a repressive effect of ERß at the promoter level of these genes. Taken together, these data show that introduction of ERß into malignant cells inhibits their growth and prevents tumor expansion by inhibiting angiogenesis. (Cancer Res 2006; 66(23): 11207-13)

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