1,25 Dihydroxyvitamin D₃: Coordinate Regulator of Active Cell Death and Proliferation in MCF-7 Breast Cancer Cells

Abstract

Maintenance of normal tissue cell number requires a net balance between the rate of cell division and the rate of cell death. The uncontrolled growth characteristic of both benign and metastatic tumors may be due to either an increase in the rate of proliferation or a decrease in the rate of cell death, or both (Williams 1991). Cell death can be classified into one of two categories: necrosis, the result of tissue insult or injury; and apoptosis, or active cell death (ACD), a process of active cellular self-destruction. ACD is an asynchronous process consisting of a series of distinct steps which are common to epithelial cells of the prostate, mammary gland, liver, and many other tissues (Bursch et al. 1990). A schematic representation of the morphology and biochemistry of ACD is shown in Fig. 1. The first visible stage of ACD in regressing mammary gland involves disruption of the cytoskeleton and condensation of intermediate filaments around the nucleus. During this stage, loss of cell to cell contacts results in the release of dying cells from the basement membrane in vivo or rounding up and detachment of adherent cells in vitro. The early apoptotic cell thus lies above the plane of the monolayer and is characterized by cytoplasmic condensation. Chromatin condensation occurs simultaneously, producing the hyperchromatic, pyknotic nucleus, which then separates into discrete masses of condensed chromatin. In some, but not all, forms of ACD, cleavage of DNA into large (50–300-kbp) fragments and further degradation into 200-bp fragments, characteristic of a nucleosome ladder, can be demonstrated (Oberhammer et al. 1993). Finally, the cell itself fragments into a number of membrane-bound vesicles called apoptotic bodies, some of which contain chromatin. In vitro, apoptotic cells and bodies can be recovered in the media, whereas in vivo, these are removed by phagocytic macrophages.