Estrogen receptor β inhibits angiogenesis and growth of T47D breast cancer xenografts

Estrogens, which are stimulators of growth of both the normal breast and malignant breast, mediate their effects through two estrogen receptors (ER), namely ER alpha and ER beta. ER alpha mediates the proliferative effect of estrogen in breast cancer cells, whereas ER beta seems to be antiproliferative. We engineered ER alpha-positive T47D breast cancer cells to express ER beta 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 ER beta. The presence of ER beta resulted in a reduction in tumor growth. Comparison of the ER beta-expressmg and non-ER beta-expressing tumors revealed that the expression of ER beta 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 beta (PDGF beta). In cell culture, with the Tet-Off-regulated ER beta-expressing cells, expression of ER beta decreased expression of VEGF and PDGF beta mRNA under normoxic as well as hypoxic conditions and reduced secreted VEGF and PDGF beta proteins in cell culture medium. Transient transfection assays with 1,026 bp VEGF and 1,006 bp PDGF beta promoter constructs revealed a repressive effect of ER beta at the promoter level of these genes. Taken together, these data show that introduction of ER beta into malignant cells inhibits their growth and prevents tumor expansion by inhibiting angiogenesis.