Regulation of the Nijmegen breakage syndrome 1 gene NBS1 by c-myc, p53 and coactivators mediates estrogen protection from DNA damage in breast cancer cells.

In mammalian cells more than 90% of double-strand breaks are repaired by NHEJ. Impairment of this pathway is associated with cell cycle arrest, cell death, genomic instability and cancer. Human diseases such as Nijmegen breakage syndrome, due to mutations in the NBS1 gene, produce defects in resection of double-strand breaks. NBS1 hypomorphic mutant mice are viable, and cells from these mice are defective in S phase and G2/M checkpoints. NBS1 polymorphisms have been associated with increased risk of breast cancer. We previously demonstrated that estradiol protected estrogen receptor (ER)-positive (+) breast cancer cell lines against double-strand breaks and cell death. We now demonstrate that protection from double-strand break damage in ER+ cells is mediated via regulation by c-myc, p53, CBP and SRC1 coactivators in intron 1 of the NBS1 gene. We concluded that NBS1 is responsible for estradiol-mediated protection from double-strand breaks in ER+ breast cancer cells.

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

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.