Effects of Estrogens on Microtubule Assembly: Significance for Aneuploidy

Abstract

The molecular mechanisms of hormonal carcinogenesis are not yet fully understood. For carcinogenic estrogens, it is likely that multiple mechanisms act together, namely, stimulation of cell proliferation, heritable reprogramming of cellular differentiation, and induction of genetic changes (1). The latter may involve numerical and/or structural chromosomal aberrations, or gene mutations. Despite efforts from several laboratories, the evidence for the induction of DNA damage and gene mutations by estrogens remains elusive. On the other hand, an increasing number of observations suggests an important role for chromosomal alterations, in particular numerical aberrations, in estrogen carcinogenesis (2). Several mechanisms have been proposed to explain the induction of aneuploidy in mitotic cells. The proposed cellular targets include spindle microtubules (MT), MT-associated proteins and regulatory molecules, kinetochores and centromeres, centrioles and centrosomes, as well as the cytoplasmic membrane and DNA (3). Several laboratories have reported colchicine-like effects when the carcinogenic estrogen diethylstilbestrol (DES) was tested in several cell systems (4–6). These effects cause inhibition of MT polymerization in cell-free conditions, as well as disruption of the mitotic spindle, and induction of aneuploidy and micronuclei (MN) in various mammalian cells. Colchicine (COL) is known to elicit its effects through noncovalent binding to the major MT protein, tubulin. We have reported the interaction of various estrogens with tubulin and its putative role in the induction of MN and aneuploidy (6–8). Herein, we summarize our recent findings on the biochemical mechanisms of known aneuploidogenic estrogens, and on the ability to induce MN and aneuploidy of recently-identified environmental estrogens and other compounds.