Transcriptional control of cell cycle progression by estrogen hormones: Regulation of cyclin D1 gene promoter activity by ER-alpha

Estrogens (Es) are mitogens for breast and uterine epithelial cells, where they exert also a tumor-promoting action that appears to be directly linked to their growth promoting effects (1-3). Although during recent years the general bases of estrogen receptor (ER) action, in particular the role of these nuclear proteins on regulation of gene transcription, have been elucidated (4), the mechanisms that underlie E control of cell proliferation still remain largely unclear, mainly due to our relatively poor knowledge of the effects of these steroids on the cell cycle regulatory pathways. In eukaryotic cells, these pathways have been found to consist of an orderly sequence of genetic and biochemical processes, controlled by extracellular mitogens as well as oncogenes, that are required for and allow completion of the different tasks leading to cell cycle progression and cell division. They include both growth regulatory or primary events, and growth regulated processes, consequent to the effects evoked in the cell by the primary events (5–6). The evident analogy of these pathways with the general mechanism of action of Es in target cells (7) raises the possibility that cell cycle regulatory (or ‘master’) genes and gene products could be target of the ER s and mediate their growth promoting actions. A better understanding of the molecular basis of the mitogenic activity of Es will be greatly fostered by the identification of such cell cycle regulatory genes and molecules, and by the subsequent elucidation of their functional interactions with the hormone and its receptors.