AbstractReduction in apoptosis has been associated with tumor metastases and response to chemotherapy in breast cancer. We examine the influence of apoptosis status and the expression of antiapoptotic proteins Bcl‐2 and Bcl‐xL on metastatic progression and response to therapy in an experimental model of breast cancer. We used human breast cancer cells (MDA‐MB 435, MDA‐MB 468 and MCF‐7) to induce orthotopic xenograft tumors in nude mice. The overexpression of Bcl‐2 or Bcl‐xL influenced tumorigenicity, 468 transfectants being less tumorigenic than control (p < 0.0001). Lung metastasis appeared at day 120 in animals injected with 435/Bcl‐2 or 435/Bcl‐xL and they showed higher metastatic activity than control 435/Neo tumors (p = 0.02). In contrast, mice with 468 tumors were followed for 1 year after tumor excision, but they did not develop metastatic foci. 435/Bcl‐2 and 435/Bcl‐xL transfectant cells bound less readily to laminin (ANOVA, p < 0.0001), fibronectin (ANOVA, p < 0.0001) and collagen type‐IV (ANOVA, p < 0.0001) than 435/Neo cells. The overexpression of antiapoptotic proteins in 435 transfectants rescued 20–40% of cells from anoikis at 64 hr in rocking conditions. In contrast, at this time only 5–10% of 468 and MCF‐7 transfectant cells were rescued. Thus, the overexpression of the Bcl‐2 or Bcl‐xL associated with the loss of apoptosis in breast cancer cells in vivo may account for their metastatic behavior. These genes increase tumor metastasis when the oncogenic background has triggered the metastatic process, in which anoikis might determine tumor progression when the life span of the cells is extended. © 2002 Wiley‐Liss, Inc.