Low pO(2) and beta-estradiol induce VEGF in MCF-7 and MCF-7-5C cells: Relationship to in vivo hypoxia

Previous work from this laboratory demonstrated that MCF-7 breast carcinoma cells grown in nude mice contained minimal hypoxia but that tamoxifen trea tment of these tumors resulted in increased hypoxia (Evans S. et al., Cance r Research, 1997). These findings led to studies exploring the link between estrogen signaling and tumor oxygenation and determining the role of VEGF in this process. The stimulation of estrogen-dependent MCF-7 breast carcino ma cells in vitro with beta -estradiol resulted in a two-fold induction of VEGF mRNA and 1.3-2-fold increase in protein, similar to what was observed when these cells were exposed to 0.1% oxygen. Furthermore, the two stimuli given together had an additive effect on (increasing) VEGF expression, sugg esting that the combination of hypoxia and estrogen may be important in upr egulating VEGF in some breast cancers. Estrogen-independent MCF-7-5C cells, developed by growing MCF-7 cells in long-term culture in estrogen-free med ia, were also studied. Using EF5, a fluorinated 2-nitroimidazole which loca lizes to hypoxic cells, MCF-7-5C tumors grown in nude mice were found to co ntain lower pO(2) levels and more hypoxic regions than similarly grown MCF- 7 tumors. We tested the hypothesis that this might be the result of defecti ve expression of VEGF in MCF-7-5C cells in response to beta -estradiol and/ or hypoxia. However, MCF-7-5C and MCF-7 cells showed a similar induction of VEGF in vitro in response to either beta -estradiol or hypoxia. Therefore, although these two cell lines grown as tumors have substantial differences in the presence and patterns of hypoxia, this could not be explained by a difference in VEGF induction.