Role of the Polyamine Pathway in the Natural History of Breast Cancer

Abstract

The diamine putrescine and the polyamines spermidine and spermine are small, aliphatic amines that play a major role in multiple cellular functions affecting proliferation and differentiation (1–3). The biosynthesis and metabolism of these compounds are quite complex and highly regulated. A simplified scheme of the polyamine metabolic pathway is illustrated in Fig. 1. Three enzymes are of critical importance in the regulation of cellular polyamine pools because of their short half-life and rapid inducibility upon exposure of a target cell to an appropriate stimulus (2,3). Ornithine decarboxylase (ODC) catalyzes the formation of putrescine from ornithine, the first and rate-limiting step in polyamine biosynthesis. Inhibition of this enzyme, particularly with the irreversible inhibitor α-difluoromethylornithine (DFMO), has been extensively used to probe basic biochemical and biological issues of polyamine physiology. S-adenosylmethionine decarboxylase (SAMDC) promotes the formation of the more distal polyamines, spermidine and spermine. Since spermidine may be the most critical polyamine controlling cell proliferation (4), regulation of the activity of this enzyme is likely to have major biological importance. Spermidine/spermine N 1 acetyl transferase (SSAT) is involved in the back conversion pathway and is the rate-limiting enzyme in polyamine catabolism. Induction of this enzyme by polyamine analogs has recently been shown to correlate with the antitumor activity of these compounds (5). The intracellular polyamine milieu of normal tissues is tightly regulated by the modulation of these critical enzymes involved in polyamine synthesis and catabolism. Derangements in the polyamine metabolic pathway are likely to play a major role in cancer since the cellular levels of polyamines and their metabolic enzymes are higher in tumors than in surrounding normal tissue (6,7). These observations point to polyamines as potential targets for anticancer therapy and chemoprevention. In this chapter, we will summarize up-to-date information on polyamine involvement in breast cancer biology with particular emphasis on their role in cell proliferation, tumor progression, and mammary carcinogenesis.