Oestrogen control of cell proliferation

The proliferation of secondary sex organs in immature or oophorectomised female vertebrates in response to oestrogens has been known for decades, indeed this response in the mouse uterus formed the basis of the first accurate bioassay for compounds with oestrogenic activity. It has also been known since the end of the last century that the ovaries, and oestrogens in particular, are intimately involved in the regulation of proliferation of human breast cancers. Despite the early development 

The concept that oestrogens stimulate cell proliferation directly arises mainly from the observation that physiological concentrations of oestrogens stimulate both the de novo and salvage pathways of DNA synthesis as well as inducing a number of enzymes intimately involved in DNA synthesis and including DNA polymerase, thymidine and uridine kinases, thymidilate synthetase and dihydrofolate reductase. There is evidence that some of these enzymes may be regulated at the transcrip- 

In addition to the regulation of growth factors, oestrogens also regulate the pro- 

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Fig. 4. Schematic model of the mechanisms of oestrogen control of cell proliferation. Three different mechanisms are illustrated. In (1) the interaction of oestrogen (E) with ER leads to increased transcription of genes whose products are directly involved in the control of cell replication. The mechanism illustrated in (2) postulates that oestrogens modulate the production of autocrine growth factors which in turn bind to growth factor receptors at the cell surface and mitogenesis occurs as a consequence of growth factor-activated metabolic pathways. The underlying hypothesis in (3) is that cells are under inhibitory (I) control by undefined molecules in the extracellular fluid and that oestrogens block the effects of these inhibitory molecules.

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