Estrogen Induces Lung Metastasis through a Host Compartment–Specific Response

Direct proliferative effects of estrogen (E 2 ) on estrogen receptor–positive tumors are well documented; however, the potential for E 2 to mediate effects selective for the host (i.e., angiogenesis, vascular permeability, or stromal effects), which influence tumor growth and/or metastasis, has received less attention. In this study, we examine the capacity for E 2 to promote tumor growth and/or metastasis independent of direct effects on tumor cells. In these studies, we distinguish host versus tumor compartment components of E 2 action in tumor growth and metastasis by analysis of E 2 -nonresponsive tumor cells implanted in ovariectomized (OVX) mice that contain s.c. implants of placebo (OVX) or E 2 -containing slow-release pellets (OVX + E 2 ). We show that the D121 lung carcinoma cell line is E 2 -nonresponsive, and following s.c. implantation in OVX versus OVX + E 2 mice, E 2 action on the host compartment leads to an increase in spontaneous metastasis but not primary tumor growth or neovascularization. Similarly, experimental lung metastasis of E 2 -nonresponsive 4T1 mammary carcinoma cells also leads to increased tumor burden in the lungs of OVX + E 2 mice. These results suggest that the E 2 status of the host compartment influences late steps in tumor cell metastasis that can provide important insights into the role of E 2 in the tumor versus host compartments. (Cancer Res 2006; 66(7): 3667-72)