Abstract 2878: HIF signaling in breast tumors controls spontaneous tumor dissemination in a site-specific manner

As tumors outgrow their blood supply, they frequently become hypoxic, activating hypoxia-inducible factor (HIF) signaling. Previous studies suggest that HIF signaling in breast cancer cells promotes lung dissemination in genetic models and bone colonization following intracardiac inoculation, but the impact of HIF signaling in the primary tumor on spontaneous dissemination to bone has never been evaluated. Thus, we hypothesized that Hif1α or Hif2α deletion in the primary tumor would reduce spontaneous dissemination to lung and bone, while deletion of Vhl (resulting in constitutive HIF signaling) would increase dissemination to distant metastatic sites. To test this, we generated MMTV-Cre.Hif1αf/f.PyMT, MMTV-Cre.Hif2αf/f.PyMT, and MMTV-Cre.Vhlf/f.PyMT mice, which spontaneously develop mammary carcinomas with conditional deletion of Hif1a, Hif2a, or Vhl, respectively. Littermate and cousin controls were used for all experiments. All mice were euthanized when the largest tumor reached 1cm in any dimension. Tumor growth was significantly delayed in Hif1α-/- (n=21) and Vhl-/- mice (n=19), while Hif2α-/- mice (n=18) had similar tumor progression compared to wildtype controls (n=19-20). Despite the delay in tumor growth, Hif1α-/- mice had greater total tumor weight (71%, p