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 HIF1α in the primary tumor on spontaneous dissemination to bone has never been evaluated. Thus, we hypothesized that HIF1α deletion in the primary tumor would reduce spontaneous dissemination to bone.
To test this, we generated MMTV-Cre.Hif1αf/f.PyMT mice, which spontaneously develop mammary carcinomas with conditional deletion of HIF1α. CreT/w/Hif1αf/f/PyMTT/w (Hif1α-/-) and Crew/w/Hif1αf/f/PyMTT/w (Hif1αf/f) littermate and cousin controls were used. Our data indicate that despite similar levels of intratumoral hypoxia (assessed by pimonidazole staining), Hif1α-/- mice (n=21 mice) had an 85% reduction in Hif1α expression, but not Hif2α, in whole mammary tumors compared to Hif1αf/f mice (n=19 mice) (p<0.0001). Surprisingly, histological inspection of lung sections revealed that Hif1α-/- mice had greater incidence of macroscopic tumor nodules (n=15/21 Hif1α-/-, n=6/19 Hif1αf/f, p<0.05), and greater average lesion number (1.9-fold increase, p<0.05) and area (2.2-fold fold increase, p<0.05), although there was no difference in proliferative capacity of the Hif1α-/- tumors (assessed by Ki-67 staining). In contrast, there was no significant difference in tumor dissemination to bone (tibia or spine), as determined by histological inspection, flow analysis for EpCAM+ tumor cells, and qPCR detection of tumor specific Pymt mRNA, nor were there differences in dissemination to liver or brain. These data suggest that blocking HIF1α signaling in primary breast tumors and metastatic tumor cells may promote tumor cell dissemination or outgrowth in the lung, where tumor cells only encounter hypoxia as they grow, but not in the physiologically hypoxic environment of the bone.