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An in vivo model of antiangiogenic therapy allowed us to identify genes upregulated by bevacizumab treatment, including Fatty Acid Binding Protein 3 (FABP3) and FABP7, both of which are involved in fatty acid uptake. In vitro, both were induced by hypoxia in a hypoxia-inducible factor-1 alpha (HIF-1 alpha)-dependent manner. There was a significant lipid droplet (LD) accumulation in hypoxia that was time and O-2 concentration dependent. Knockdown of endogenous expression of FABP3, FABP7, or Adipophilin (an essential LD structural component) significantly impaired LD formation under hypoxia. We showed that LD accumulation is due to FABP3/7-dependent fatty acid uptake while de novo fatty acid synthesis is repressed in hypoxia. We also showed that ATP production occurs via beta-oxidation or glycogen degradation in a cell-type-dependent manner in hypoxia-reoxygenation. Finally, inhibition of lipid storage reduced protection against reactive oxygen species toxicity, decreased the survival of cells subjected to hypoxia-reoxygenation in vitro, and strongly impaired tumorigenesis in vivo.
The female sex hormone 17beta-estradiol, produced naturally in the body, seems to play an important role in the development of breast cancer, since (i) it can be activated to reactive metabolites, which are known to damage DNA and (ii) the stimulation of the estrogen receptor alpha by 17beta-estradiol enhances cell proliferation. Both processes together increase mutation frequency and subsequently lead to transformation of epithelial cells. Therefore, the aim of this work was to characterize the influence of polymorphisms and lifestyle factors on 17beta-estradiol metabolism in normal mammary gland tissue. [...]
In sum, the tissue specific 17beta-estradiol metabolism was described in mammary gland tissue homogenate, whereas differences in proliferation of epithelial cells were only reflected in isolated epithelial cells. Factors associated with breast cancer risk (age, BMI and age-related changes in mammary gland morphology) were shown to affect 17beta-estradiol tissue levels.
The 17beta-estradiol mediated genotoxicity was evaluated using bioinformatically calculated
DNA adduct fluxes, which were predominately influenced by individual mRNA patterns rather than individual genotypes and (DNA adduct fluxes) were correlated with known breast cancer risk factors (age, parity, BMI and polymorphism of glutathione-S-transferase theta 1).