Apoptosis in normal and neoplastic mammary gland development

Abstract

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 undergoes apoptosis as the mammary gland regresses and is reorganized for another 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 and for approaching the failure of apoptosis found in mammary hyperplasia. Morphological studies and gene expression have suggested that apoptosis during involution is comprised of two phases: an early limited apoptosis in response to hormone ablation and later protease promoted widespread apoptosis in response to altered cell-matrix interactions and loss of anchorage. We examined protein expression during involution for changes associated with loss of hormone stimulation and altered cell-matrix interactions. One of the proteins whose expression is able to inhibit apoptosis, and is altered during mammary epithelial cell was the serine-threonine protein kinase, Akt 1. Akt 1 activation is common to hormone, growth factor, and anchorage-mediated survival of epithelial cells. We found regulated expression of activated Akt 1 in the mammary gland during involution. Akt 1 activation peaked in pregnancy and lactation, and decreased significantly during apoptosis in mammary involution. Mechanisms of Akt 1 action include modulation of the ratio bcl-2 family members implicated in control of apoptosis. Bcl-2 family proteins were also expressed in pattern consistent with Akt 1 regulation. These observations led us to examine expression of activated Akt 1 and bcl-2 family proteins in premalignant hyperplasias. Akt 1 activation was increased; expression of anti-apoptotic proteins bcl-2 and bcl-x was strongly increased while pro-apoptotic bax was greatly diminished in three different lines of transplantable premalignant mammary hyperplasia. This data suggest that activation of Akt 1 by hormone- or anchorage-mediated pathways regulates survival of mammary epithelium and can contribute to initiation of neoplasia. These data suggest that perturbation of normal cell turnover can contribute to initiation of neoplasia.