Campbell-McNulty, M.J.; (2008) Isoflavone effects on insulin like growth factors and breast cancer. Doctoral thesis , University of London.

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Abstract

An increased concentration of insulin-like growth factor-1 (IGF-1) is recognized to be an independent risk factor for pre-menopausal breast cancer. Tamoxifen is thought to initially reduce IGF-1 concentrations and increase levels of the IGF binding proteins 1 and 3. Isoflavones are oestrogen-like plant compounds, which may, because of their structural similarities to tamoxifen, also alter IGF status. This thesis first compares IGF-1, IGF binding protein 1(BP-1) and IGF binding protein 3 (BP-3) levels in breast cancer patients (n=14) compared with control subjects (n=23) and then assesses the effect of tamoxifen on IGF status after 9, 18 and 27 months of treatment. Concentrations of IGF-1, BP-1 and BP-3 at baseline did not differ between cases and controls. However on tamoxifen treatment, BP-1 and BP-3 were both significantly increased after 18 and 27 months while the IGF-1/BP-3 ratio was significantly decreased after 9 and 18 months. A feasibility study was then conducted to compare the effects of acute (single 80 mg load) versus chronic (80 mg/day for 7 days) administration of isoflavone- containing soy and linseed cereal bars on IGF-1, IGFBP-1 and IGFBP-3 in healthy female volunteers (n=10). Assays were established for the analyses of serum IGF-1, BP1 and BP3 concentrations and GCMS analysis of isoflavones in urine. Concentrations of IGF-1 were unchanged following the single 80 mg load. However, IGF-1 and BP-3 concentrations were significantly elevated after a week of supplementation with the soy and linseed bar. A larger study was then carried out to assess the effect of one-month isoflavone supplementation (80 mg/d) in tablet form, on IGF status in healthy pre- (n=16) and post-menopausal (n=7) women. This was a randomized, placebo-controlled crossover study with a minimum two-month washout period. Hormonal, antioxidant and lipid altering effects of the supplement were also examined, as was background diet. For pre-menopausal subjects, while there was an effect of time on IGF-1 (p=0.005), BP-1 (p=0.004), and BP-3 (p<0.001) confirming that IGF profile is influenced by menstrual cycle, this did not differ between placebo and isoflavone supplement. When the change in IGF-1 over the whole supplementation period was compared between the supplement and placebo phases, there was a non-significant reduction in change in IGF-1 (p=0.06) on isoflavone supplement compared to placebo. However, this may have been due to the non-significantly higher baseline concentrations of IGF-1 during the supplement phase. In post-menopausal subjects, there was no effect of isoflavone supplementation in comparison with placebo on IGF-1, BP-1 or BP-3. Finally, experiments were done in vitro to study the effect of isoflavones on DNA synthesis and proliferation in ERa positive MCF-7 and ERa negative MDA-MB 231 human breast cancer cells. In MCF-7 cells, low concentrations of isoflavones (0.1uM-10uM) stimulated DNA synthesis while high concentrations of genistein and equol were able to inhibit DNA synthesis with IC50 values of 93uM and 55uM respectively compared with 1.17uM tamoxifen. In MDA-MB231 cells the Isoflavones did not stimulate DNA synthesis at any concentrations but significantly inhibited DNA synthesis with IC50 values of 114uM, 14.1 uM and 14.55uM for daidzein, genistein and equol respectively compared with 1.35uM tamoxifen. This work suggests that isoflavone supplementation may alter IGF profile in pre menopausal women, and could suggest a role for these dietary compounds in breast cancer prevention. This should be further investigated in long term intervention studies with isolated isoflavone supplements.

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