ABSTRACT
Women approaching menopause increasingly investigate alternatives to hormone replacement therapy. Plant phytoestrogens are being promoted as "natural" alternatives but there is a lack of substantive data to advocate their safe use in breast cancer patients receiving tamoxifen (TAM), or in those who have relapsed. The aim of our study was to investigate the proliferative effects and mode of action of the phytoestrogens genistein, daidzein and coumestrol on TAM-sensitive (-s) and resistant (-r) breast cancer cells under in vitro conditions designed to mimic the hormonal environment of the pre- and post-menopausal breast. At physiological concentrations (<10 microM) and under reduced estrogen (E2) conditions, genistein was mitogenic to TAM-s cells with TAM-r cells generally refractory. Daidzein and coumestrol were growth stimulatory irrespective of TAM sensitivity. Transcriptional activity was ERE-mediated. Combining phytoestrogens with E2 (simulating the pre-menopausal breast environment) had no effect on growth of TAM-s or TAM-r cells. Addition of 4-HT mimicked the hormonal environment in post-menopausal breast cancer patients receiving TAM. The growth inhibitory effects of 4-HT were abrogated in TAM-s cells when combined with genistein and coumestrol, and to a lesser extent, daidzein, where significant growth stimulatory effects were observed. In TAM-r cells, proliferation did not exceed control values. At phytoestrogen concentrations above 10 microM, growth inhibitory effects were seen, irrespective of estrogenic environment or cell sensitivity to TAM. Our in vitro data suggests that phytoestrogens could have potentially adverse mitogenic effects on tumour cells and should probably be avoided by patients who remain sensitive to TAM or in those with pre-existing and possibly undiagnosed breast tumours.
Subject(s)
Breast Neoplasms/drug therapy , Phytoestrogens/pharmacology , Tamoxifen/pharmacology , Antineoplastic Agents, Hormonal/pharmacology , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Cell Line, Tumor , Cell Proliferation/drug effects , Coumestrol/pharmacology , Dose-Response Relationship, Drug , Drug Resistance, Neoplasm , Estrogen Receptor alpha/metabolism , Estrogen Receptor beta/metabolism , Estrogens/pharmacology , Female , Gene Expression/drug effects , Genistein/pharmacology , Humans , Isoflavones/pharmacology , Luciferases/genetics , Luciferases/metabolism , Receptors, Progesterone/metabolism , Response Elements/genetics , Tamoxifen/analogs & derivatives , TransfectionABSTRACT
Phytoestrogens are polyphenol compounds of plant origin that exhibit a structural similarity to the mammalian steroid hormone 17beta-oestradiol. In Asian nations the staple consumption of phyto-oestrogen-rich foodstuffs correlates with a reduced incidence of breast cancer. Human dietary intervention trials have noted a direct relationship between phyto-oestrogen ingestion and a favourable hormonal profile associated with decreased breast cancer risk. However, these studies failed to ascertain the precise effect of dietary phyto-oestrogens on the proliferation of mammary tissue. Epidemiological and rodent studies crucially suggest that breast cancer chemoprevention by dietary phyto-oestrogen compounds is dependent on ingestion before puberty, when the mammary gland is relatively immature. Phyto-oestrogen supplements are commercially marketed for use by postmenopausal women as natural and safe alternatives to hormone replacement therapy. Of current concern is the effect of phyto-oestrogen compounds on the growth of pre-existing breast tumours. Data are contradictory, with cell culture studies reporting both the oestrogenic stimulation of oestrogen receptor-positive breast cancer cell lines and the antagonism of tamoxifen activity at physiological phyto-oestrogen concentrations. Conversely, phyto-oestrogen ingestion by rodents is associated with the development of less aggressive breast tumours with reduced metastatic potential. Despite the present ambiguity, current data do suggest a potential benefit from use of phyto-oestrogens in breast cancer chemoprevention and therapy. These aspects are discussed.
Subject(s)
Anticarcinogenic Agents/therapeutic use , Breast Neoplasms/prevention & control , Enzyme Inhibitors/therapeutic use , Isoflavones/therapeutic use , Plant Preparations/therapeutic use , Adolescent , Adult , Age Factors , Aged , Animals , Anticarcinogenic Agents/chemistry , Anticarcinogenic Agents/pharmacology , Antineoplastic Agents, Hormonal/antagonists & inhibitors , Antineoplastic Agents, Hormonal/therapeutic use , Asia/epidemiology , Asia/ethnology , Breast Neoplasms/drug therapy , Breast Neoplasms/epidemiology , Child , Emigration and Immigration , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Estrogens , Feeding Behavior , Female , Humans , Infant , Isoflavones/adverse effects , Isoflavones/chemistry , Isoflavones/pharmacology , Mammary Neoplasms, Experimental/chemically induced , Mammary Neoplasms, Experimental/prevention & control , Mice , Middle Aged , Neoplasm Proteins/antagonists & inhibitors , Neoplasms, Hormone-Dependent/drug therapy , Neoplasms, Hormone-Dependent/prevention & control , Phytoestrogens , Plant Preparations/adverse effects , Plant Preparations/chemistry , Plant Preparations/pharmacology , Postmenopause , Premenopause , Prevalence , Protein-Tyrosine Kinases/antagonists & inhibitors , Receptors, Estrogen/drug effects , Receptors, Estrogen/metabolism , Signal Transduction/drug effects , Structure-Activity Relationship , United States/epidemiologyABSTRACT
The four-day biennial 8th Nottingham Breast Cancer Conference held at the East Midlands Conference Centre, University of Nottingham, UK (16-19 September 2003) once again proved to be a successful event. Recent advances in clinical and scientific research were presented to an international audience, covering a broad spectrum of breast cancer issues including prediction, diagnosis and treatment. Delegates were encouraged to participate in workshop sessions, which allowed the comprehensive discussion of existing and promising future advances in breast cancer care.
