E-CADHERIN EXPRESSION IN HUMAN BREAST-CANCER CELLS SUPPRESSES THE DEVELOPMENT OF OSTEOLYTIC BONE METASTASES IN AN EXPERIMENTAL METASTASIS MODEL

The molecular mechanisms by which human cancer cells spread to bone ar e largely unexplored. The process likely involves cell adhesion molecu les (CAMs) that are responsible for hemophilic and heterophilic cell-c ell interactions. One relevant CAM may be the calcium-dependent transm embrane glycoprotein E-cadherin. To investigate the involvement of E-c adherin in breast cancer metastasis to bone, we used an in vivo model in which osteolytic bone metastases preferentially occur after injecti ons of cancer cells directly into the arterial circulation through the left ventricle of the hearts of nude mice. We have found that E-cadhe rin-negative human breast cancer cells MDA-MB-231 (MDA-231) develop ra diographically detectable multiple osteolytic bone metastases and cach exia in this model. However, MDA-231 breast cancer cells that were tra nsfected with E-cadherin cDNA showed a dramatically impaired capacity to form osteolytic metastases and induce cachexia. Histological and hi stomorphometrical analyses of bones of mice bearing mock-transfected M DA-231 revealed aggressive metastatic tumor, whereas metastatic tumor burden was significantly decreased in the bones of mice bearing E-cadh erin-expressing MDA-231. Nude mice bearing E-cadherin-transfected MDA- 231 breast cancer cells survived longer than mice bearing mock-transfe cted MDA-231 breast cancer cells. Anchorage-dependent and -independent growth in culture and tumor enlargement in the mammary fat pad of nud e mice were unchanged between mock-transfected and E-cadherin-expressi ng MDA-231, suggesting that these differences in metastatic behavior a re not due to an impairment of cell growth and tumorigenicity. Our res ults show the suppressive effects of E-cadherin expression on bone met astasis by circulating breast cancer cells and suggest that the modula tion of expression of this CAM may reduce the destructive effects of b reast cancer cells on bone.