Authors: Vikas Sehdev, James C.K. Lai and Alok Bhushan
Affiliation:
Title: An isoflavone Biochanin-A, modulates growth promoting, survival and antioxidant pathways in HER positive breast cancer cells
Abstract: In this report we show the effects of Biochanin-A (Bio-A, a dietary isoflavone) and manganese (Mn, a trace lement) alone and in combination on Human Epidermal Growth Factor Receptor-2 (HER-2) activation, initiation of downstream signaling pathways and antioxidant enzyme activity in SK-BR-3 breast cancer cells. Consumption of diet rich in fruits, green leafy vegetables and soy-based products has been correlated with reduced breast cancer incidence. Since such a diet contains both Bio-A (a soy isoflavone with antioxidant properties) and Mn, we hypothesized that treatment of breast cancer cells with Bio-A alone and in combination with Mn results in reduced breast cancer cell survival. To test our hypothesis, we carried out cell survival analysis with Bio-A and Mn alone and in combination. Treatment of SK-BR-3 cancer cells with combinations of Bio-A and Mn (Bio-A+Mn; 50+0.5µM→81.679±1.48, p<0.0001; 80+0.5µM→32.904±1.15, p<0.0001) led to increased inhibition of cell survival as compared to that of Bio-A and Mn alone. Increased lactate dehydrogenase (LDH) release by SK-BR-3 cells in the medium upon combination treatment compared to Bio-A (50µM) or Mn (0.5µM) treatment alone suggests necrosis as one cell death mechanism. HER-2 receptor overexpression and/or activation (observed in about 30% of breast cancer cases) has been correlated with poor prognosis and aggressive form of breast cancer. Moreover endogenous levels of ROS have been shown to facilitate receptor activation and downstream signaling. Therefore we evaluated the effect of Bio-A alone and in combination with Mn on HER-2 receptor activation, downstream signaling pathways (Akt, Erk and mTOR) and superoxide dismutase (SOD, an antioxidant enzyme) activity. Our data indicates inhibition of HER-2 receptor activation, downstream signaling pathways and reduced SOD activity as possible molecular mechanisms for inhibition of SK-BR-3 breast cancer cell survival. These observations suggest treatment with Bio-A combined with Mn may provide an enhanced anticancer effect. (This study was supported by FRC Grant # 681-507-01)