The extracellular matrix (ECM) suppresses apoptosis in mammary epithelial cells through integrin-dependent regulation of ICE (interleukin-1 β converting enzyme). Apoptosis, a key process in development and tissue regeneration, is regulated by specific genes such as BCL-2 and ICE. The ECM, but not fibronectin or collagen, suppresses apoptosis in mammary epithelial cells in vitro and in vivo. Apoptosis was induced by antibodies to β1 integrins or by overexpression of stromelysin-1, which degrades the ECM. Expression of ICE correlated with ECM loss, and inhibitors of ICE activity prevented apoptosis. These results suggest that ECM regulates apoptosis in mammary epithelial cells through integrin-dependent negative regulation of ICE expression. Growth, differentiation, and apoptosis are crucial for normal development and tissue-specific function. The ECM influences the apoptotic program in mammalian cells. Mammary gland alveolar morphology and milk-specific gene expression depend on laminin-rich ECM. Involution of the gland, following the lactational phenotype, is characterized by ECM degradation by metalloproteinases and is accompanied by apoptosis. Cell attachment via integrin-ECM interactions suppresses apoptosis in short-term cultures. To determine whether ECM regulates apoptosis, CID-9 mammary epithelial cells were compared on plastic versus exogenous basement membrane ECM. Cells on plastic showed apoptosis features, while those on ECM did not. ECM-derived signals suppress apoptosis, as shown by the addition of anti-β1 integrin antibodies, which increased apoptosis. Stromelysin-1 overexpression induced apoptosis, and proteolytic destruction of the ECM led to apoptosis in culture and in vivo. Apoptosis in MECs was mediated by ICE, as shown by crmA and BACMK treatments. ICE expression was induced during involution, and its expression was suppressed by ECM. The presence of ECM prevents apoptosis by suppressing ICE expression. The study concludes that ECM, through integrin receptors, directs MECs to maintain the differentiated state and suppresses ICE expression, preventing apoptosis. The proteolytic degradation of ECM during involution leads to the loss of the differentiated state, induction of ICE expression and activity, and ultimately apoptotic cell death. The study highlights the importance of specialized β1 integrin-mediated signals from specific ECM components in MEC survival.The extracellular matrix (ECM) suppresses apoptosis in mammary epithelial cells through integrin-dependent regulation of ICE (interleukin-1 β converting enzyme). Apoptosis, a key process in development and tissue regeneration, is regulated by specific genes such as BCL-2 and ICE. The ECM, but not fibronectin or collagen, suppresses apoptosis in mammary epithelial cells in vitro and in vivo. Apoptosis was induced by antibodies to β1 integrins or by overexpression of stromelysin-1, which degrades the ECM. Expression of ICE correlated with ECM loss, and inhibitors of ICE activity prevented apoptosis. These results suggest that ECM regulates apoptosis in mammary epithelial cells through integrin-dependent negative regulation of ICE expression. Growth, differentiation, and apoptosis are crucial for normal development and tissue-specific function. The ECM influences the apoptotic program in mammalian cells. Mammary gland alveolar morphology and milk-specific gene expression depend on laminin-rich ECM. Involution of the gland, following the lactational phenotype, is characterized by ECM degradation by metalloproteinases and is accompanied by apoptosis. Cell attachment via integrin-ECM interactions suppresses apoptosis in short-term cultures. To determine whether ECM regulates apoptosis, CID-9 mammary epithelial cells were compared on plastic versus exogenous basement membrane ECM. Cells on plastic showed apoptosis features, while those on ECM did not. ECM-derived signals suppress apoptosis, as shown by the addition of anti-β1 integrin antibodies, which increased apoptosis. Stromelysin-1 overexpression induced apoptosis, and proteolytic destruction of the ECM led to apoptosis in culture and in vivo. Apoptosis in MECs was mediated by ICE, as shown by crmA and BACMK treatments. ICE expression was induced during involution, and its expression was suppressed by ECM. The presence of ECM prevents apoptosis by suppressing ICE expression. The study concludes that ECM, through integrin receptors, directs MECs to maintain the differentiated state and suppresses ICE expression, preventing apoptosis. The proteolytic degradation of ECM during involution leads to the loss of the differentiated state, induction of ICE expression and activity, and ultimately apoptotic cell death. The study highlights the importance of specialized β1 integrin-mediated signals from specific ECM components in MEC survival.