Apoptosis in normal and neoplastic mammary gland development

Apoptosis plays important roles in mammary development from early embryonic formation of the mammary gland to the regression that follows cessation of cycling. The most dramatic occurrence of apoptosis is found during mammary involution. Most of the secretory epithelium in the lactating breast under goes apoptosis as the mammary gland regresses and is reorganized for anothe r cycle of lactation. We used the morphology, biochemical changes, and gene expression detected in apoptotic mammary epithelium during involution as a model for studying cell death during other stages of mammary development a nd for approaching the failure of apoptosis found in mammary hyperplasia. M orphological studies and gene expression have suggested that apoptosis duri ng involution is comprised of two phases: an early limited apoptosis in res ponse to hormone ablation and later protease promoted widespread apoptosis in response to altered cell-matrix interactions and loss of anchorage. We e xamined protein expression during involution for changes associated with lo ss of hormone stimulation and altered cell-matrix interactions. One of the proteins whose expression is able to inhibit apoptosis, and is altered duri ng mammary epithelial cell was the serine-threonine protein kinase, Akt 1. Akt 1 activation is common to hormone, growth factor, and anchorage-mediate d survival of epithelial cells. We found regulated expression of activated Akt 1 in the mammary gland during involution. Akt 1 activation peaked in pr egnancy and lactation, and decreased significantly during apoptosis in mamm ary involution. Mechanisms of Akt 1 action include modulation of the ratio bcl-2 family members implicated in control of apoptosis. Bcl-2 family prote ins were also expressed in pattern consistent with Akt 1 regulation. These observations led us to examine expression of activated Akt 1 and bcl-2 fami ly proteins in premalignant hyperplasias. Akt 1 activation was increased; e xpression of anti-apoptotic proteins bcl-2 and bcl-x was strongly increased while pro-apoptotic bar was greatly diminished in three different lines of transplantable premalignant mammary hyperplasia. This data suggest that ac tivation of Akt 1 by hormone- or anchorage-mediated pathways regulates surv ival of mammary epithelium and can contribute to initiation of neoplasia. T hese data suggest that perturbation of normal cell turnover can contribute to initiation of neoplasia. (C) 2001 Wiley-Liss, Inc.