Truncation of the β-catenin binding domain of E-cadherin precedes epithelial apoptosis during prostate and mammary involution

A potential target of hormone action during prostate and mammary involution is the intercellular junction of adjacent secretory epithelium. This is supported by the long-standing observation that one of the first visible stages of prostate and mammary involution is the disruption of interepithelial adhesion prior to the onset of apoptosis. In a previous study addressing this aspect of involution, we acquired compelling evidence indicating that the disruption of E-cadherin-dependent adhesion initiates apoptotic programs during prostate and mammary involution. In cultured prostate and mammary epithelial cells, inhibition of E-cadherin-dependent aggregation resulted in cell death following apoptotic stimuli. Loss of cell- cell adhesion in the nonaggregated population appeared to result from the rapid truncation within the cytosolic domain of the mature, 120-kDa species of E-cadherin (E-cad¹²⁰). Immunoprecipitations from cell culture and involuting mammary gland demonstrated that this truncation removed the β- catenin binding domain from the cytoplasmic tail of E-cadherin, resulting in a non-β-catenin binding, membrane-bound 97-kDa species (E-cad⁹⁷) and a free cytoplasmic 35-kDa form (E-cad³⁵) that is bound to β-catenin. Examination of E-cadherin expression and cellular distribution during prostate and mammary involution revealed a dramatic reduction in junctional membrane staining that correlated with a similar reduction in E-cad¹²⁰ and accumulation of E-cad⁹⁷ and E-cad³⁵. The observation that E-cadherin was truncated during involution suggested that hormone depletion activated the same apoptotic pathway in vivo as observed in vitro. Based on these findings, we hypothesize that truncation of E-cadherin results in the loss of β- catenin binding and cellular dissociation that may signal epithelial apoptosis during prostate and mammary involution. Thus, E-cadherin may be central to homeostatic regulation in these tissues by coordinating adhesion- dependent survival and dissociation-induced apoptosis.