Haploinsufficiency of the Nijmegen breakage syndrome 1 gene increases mammary tumor latency and metastasis

Abstract

Abstract. Human diseases such as Nijmegen breakage syndrome due to mutations in the NBS1 gene result in defects in resection of double strand breaks. NBS1 functions as part of the MRN complex which functions in homologous recombination and non-homologous end joining. NBS is a rare human autosomal recessive disorder caused by hypomorphic mutations. At the cellular level, NBS is characterized by radiosensitivity, chromosomal breakage and defective cell cycle checkpoints. NBS1 null mutations result in early embryonic lethality in mice, but NBS1 hypomorphic mutants are viable. Cells from these mice are defective in S phase and G2/M checkpoints. In humans, NBS1 polymorphisms have been associated with increased risk of breast cancer. MRN expression was reduced in the majority of breast tumors, and low expression of MRN correlated with increased histologic grade and estrogen receptor negativity. While these studies have shown NBS1 to be important in clinical outcomes of patients with breast cancer, mammary tumors are rare in the NBS1 haploinsufficient mouse. To better understand the role of NBS1 in mammary tumorigenesis, we examined the NBS1+/-;MMTV-neu mouse model. Mammary tumor latency was markedly increased in NBS1+/-;neu mice compared to NBS1+/+;neu control animals. This effect was due to increased apoptosis in early NBS1+/-;neu mammary tumors. However, NBS1+/-;neu mammary tumors were highly metastatic and demonstrated clear differences in gene expression profiles compared to control tumors. We concluded that NBS1 haploinsufficiency results in increased mammary tumor latency and metastasis.

DNA Damage Response Genes and the Development of Cancer Metastasis

“…In addition, it has recently been demonstrated that although NBS1 haploinsufficiency leads to increased mammary tumor latency in the MMTV-neu mouse model, the tumors that do form are characterized by high metastatic potential (240), further highlighting the role of NBS1 in tumor metastasis.…”

Deficiency of the DNA repair protein nibrin increases the basal but not the radiation induced mutation frequency in vivo

“…Clearly nibrin is required for radiation induced apoptosis and the p70-nibrin product of the hypomorphic c.657 661del5 mutation is sufficient to uphold this function. Indeed, even enhanced apoptosis has been previously reported in irradiated NBS patient cells [33] and in a haploinsufficient mouse model [34]. Furthermore, the early embryonic lethality of Nbn null mutants was due to massive apoptosis [8].…”

“…Examining mice heterozygous for a null mutation, Nbn ins6 , indicated an increased tumour occurrence without loss of the remaining wild type allele [8]. Similarly, the same Nbn ins6 mutation on a mammary tumour prone MMTV-neu background lead to the development of highly metastatic mammary tumours [34]. We have examined here the mutation frequency in mice heterozygous for a null mutation in Nbn and although we find no evidence for an increased basal mutation rate, we do see a shift in mutation spectrum in comparison to wild type mice.…”