Analysis Of The Ikkβ/Nf-Κb Signaling Pathway During Embryonic Angiogenesis And Tumorigenesis Of Breast Cancer

The NF-κB signaling pathway regulates immune and inflammatory responses, cellular growth, survival, differentiation and development. In this study, the functions of IκB kinase (IKK)β in angiogenesis during mouse development were examined. Conditional disruption of the Ikkβ locus in endothelial cells using the well-characterized Tie2-Cre transgene resulted in embryonic lethality between E13.5 and E15.5. Examination of the mutant embryos revealed that, while deletion of Ikkβ occurred in endothelial cells throughout the embryo, only the vascular network in the fetal liver was affected. Disruption of the fetal liver vasculature was accompanied by decreased cell proliferation and increased apoptosis of hepatocytes, but hematopoiesis was not affected. Increased apoptosis was not observed outside of fetal liver in the mutant embryos. These results indicate that the IKKβ/NF-κB pathway plays a previously unappreciated role in development of the sinusoidal vasculature in the fetal liver and, additionally, that this pathway is critical in the crosstalk between endothelial cells and hepatocytes during mouse development.

Breast cancer is the second leading cause of cancer-related mortality in women. It is still unclear which of the changes in breast tumors are likely to lead to invasion and metastasis at the molecular level. Angiogenesis and invasiveness, two major traits contributing to tumor aggressiveness, are partially regulated by NF-κB. In this project, we carried out in vivo approaches using PyMT transgenic mouse model of breast cancer to study the functions of NF-κB in tumorigenesis of breast cancer. Mammary gland epithelia-specific MMTV-Cre and macrophage-specific Lys-Cre were used to delete Ikkβ, respectively in these compartments to study functions of NF-κB in microenvironment of breast cancer. Pulmonary metastasis was reduced by 5.3-fold in IKKβ^F/F/PyMT/Lys-Cre animals. However, tumor incidence or tumor burden was not affected in both groups. Inefficient recombination of the conditional allele could provide an explanation for the results, since Ikkβ was only partially deleted in both IKKβ^F/F/PyMT/Lys-Cre and IKKβ^F/F/PyMT /MMTV-Cre animals. In order to increase knockout efficiency, a conventional allele was produced by using Sox2-Cre. The studies of Ikkβ in breast cancer tumorigenesis are still on going.