CYCLIN GENE-EXPRESSION AND GROWTH-CONTROL IN NORMAL AND NEOPLASTIC HUMAN BREAST EPITHELIUM

Recent advances in defining the molecular mechanisms of cell cycle control in eukaryotes provide a basis for better understanding the hormonal control of cell proliferation in normal and neoplastic breast epithelium. It is now clear that a number of critical steps in cell cycle progression are controlled by families of serine/threonine kinases, the cdks. These kinases are activated by interactions with various cyclin gene products which form the regulatory subunits of the kinase complexes. Several families of cyclins control cell cycle progression in G(1) phase, cyclins C, D and E, or in S, G(2) and mitosis, cyclins A and B. Recent studies have defined the expression and regulation of cyclin genes in normal breast epithelial cells and in breast cancer cell lines. Following growth arrest of T-47D breast cancer cells by serum deprivation restimulation with insulin results in sequential induction of cyclin genes. Cyclin D1 mRNA increases within 1 h of mitogenic stimulation and is followed by increased expression of cyclins D3 and E in G(2) phase, cyclin A in late G(2)/early S phase and cyclin B1 in G(2). Similar results were observed following epidermal growth factor stimulation of normal breast epithelial cells. Other hormones-oestrogens and progestins-and growth factors-insulin-like growth factor-I and basic fibroblast growth factor-with actions in G(1) were also investigated for their effects on G(1) cyclin gene expression. In all cases there was an excellent correlation between the induction of cyclin D1 mRNA and subsequent entry into S phase. Furthermore, growth inhibition by antioestrogens and concurrent G(1) arrest were preceded by an acute decrease in cyclin D1 gene expression. These observations suggest a likely role for cyclin D1 in mediating many of the known hormonal effects on cell proliferation in breast epithelial cells.