E-cadherin mediates aggregation-dependent survival of prostate and mammaryepithelial cells through the retinoblastoma cell cycle control pathway

E-cadherin and the retinoblastoma tumor suppressor (Rb) are traditionally a ssociated with diverse regulatory aspects of cell growth and differentiatio n, However, we have discovered new evidence, which suggests that these prot eins are functionally linked in a physiologic pathway required for cell sur vival and programmed cell death. pharmacological activation of protein kina se C (PKC) or inducible overexpression and activation of the alpha isozyme of PRC (PHC alpha) resulted in approximately 60% apoptosis of mammary and p rostate epithelial cells, Interestingly, the surviving cells had undergone dramatic aggregation concurrent with increased E-cadherin expression. When aggregation was inhibited by the addition of an E-cadherin-blocking antibod y, apoptosis increased synergistically, We hypothesized that survival of th e aggregated population was associated with contact-inhibited growth and th at apoptosis might result from aberrant growth regulatory signals in non-ag gregated, cycling cells. This hypothesis was confirmed by experiments that demonstrated that E-cadherin-dependent aggregation resulted in Rb-mediated GI arrest and survival, Immunoblot analysis and Bow cytometry revealed that hypophosphorylated Rb was present in non-aggregated, S phase cultures conc urrent with synergistic cell death. We have also determined that the loss o f membrane E-cadherin and subsequent hypophosphorylation of Rb in luminal e pithelial cells preceded apoptosis induced by castration. These findings pr ovide compelling evidence that suggests that E-cadherin-mediated aggregatio n results in Rb activation and G(1), arrest that is critical for survival o f prostate and mammary epithelial cells, These data also indicate that Rb c an initiate a fatal growth signal conflict in non-aggregated, cycling cells when the protein is hypophosphorylated as these epithelial cells enter S p hase.