Oestrogen cell proliferation

Drugs that can be used to control tumour cell proliferation inhibit a variety of enzymes, including thymidylate synthase and topoisomerase (Chapter 20). The enzyme aromatase converts a ring in a steroid to an aromatic ring. It converts, for example, adrenal steroid hormones into female sex hormones, which bind to oestrogenic receptors in the ovary or breast and increase the risk of ovarian or breast cancer. Aromatase inhibitors are used to treat patients with breast or ovarian cancers that are sensitive to oestrogen. Unfortunately, none of the inhibitors is specific for enzymes in tumour cells and they can therefore have severe side-effects (Chapter 21). 

From the earlier work discussed at the 1978 Cold Spring Harbor Meeting on Cell Proliferation there has developed a broad field concerned with the study of growth factors and hormones and their effects on cell growth and differentiation. This area is considered in more detail in Chapter 2 and is of enormous clinical importance for the treatment of cancer. As well as the work on peptide hormones much work has focused on the use of MCF-7 and ZR 75.1 cell lines which were isolated from human breast tumour tissue (Lippman et al., 1977 Engel et al., 1978). These cells respond to oestrogen treatment, but the system is not as simple as first thought and may involve paracrine responses (Leake, 1988). 

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.

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-... 

EGF-RTK [antibacterial, antifungal, oestrogenic inhibits EST-R positive breast cancer cell proliferation] EGF-RTK (19) (uncoupler)... 

AROM, HISK, 17PHSOR, lipase, peroxidase, PK) [phytooestrogen inhibits breast cancer cell proliferation, antifungal, oestrogenic]... 

Genistein (but not other phyto-oestrogens) inhibits cell proliferation by inhibiting the tyrosine kinase activity of the epithelial growth factor receptor. 

PANNO M L, SALERNO M, PEZZI V, SISCI D, MAGGIOLINI M, MAURO L, MORRONE E G, ANDO S (1996) Effect of oestradiol and insulin on the proliferation pattern of oestrogen and progesterone receptor contents in MCF-7 cells. J Cancer Res Clin Oncol. 122 745-9. 

By contrast, other compounds in food may decrease cancer risk (Table 21.7). Free radical scavengers such as the antioxidants, vitamins E and C, carotenoids and fla-venoids have anti-cancer activity, while vitamins A and D and other retinoids may encourage a cell to differentiate rather than proliferate (Box 21.4). Plant oestrogens in soya prodncts may be protective since they compete with human oestrogens for the oestrogen receptors in breast and ovary bnt elicit no response. 

Guthrie, N., Gapor, A., Chambers, A.F. and Carroll, K.K. (1997) Palm oil tocotrienols and plant flavanoids act synergistically with tamoxifen in inhibiting proliferation and growth of oestrogen receptor negative MDA-MB-435 and positive MCF-7 human breast cancer cells. Asia Pacific J. Clin. Nutr., 6, 41-45. 

Freudenstein, J., and C. Bodinet. 1999. Influence of an isopropa-nolic aqueous extract of Cimicifuga racemosa rhizoma on the proliferation of MCF-7 cells (abstract). Paper read at 23rd Int. LOF-Symposium on Phyto-Oestrogens, at University of Gent, Belgium. 

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