Patients with TNBC have worse survival than patients with non-TNBC. The new AJCC staging manual should consider breast cancer biomarker information.

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Patients with tumors that are ER-positive 1%-9% have clinical and pathologic characteristics different from those with tumors that are ER-positive ≥10%. Similar to patients with ER-negative tumors, those with ER-positive 1%-9% disease do not appear to benefit from endocrine therapy; further study of its clinical benefit in this group is warranted. Also, there is a need to better define which patients of this group belong to basal or luminal subtypes.

In vitro studies have implicated nuclear respiratory factor 1 (NRF-1) in the transcriptional expression of nuclear genes required for mitochondrial respiratory function, as well as for other fundamental cellular activities. We investigated here the in vivo function of NRF-1 in mammals by disrupting the gene in mice. A portion of the NRF-1 gene that encodes the nuclear localization signal and the DNA-binding and dimerization domains was replaced through homologous recombination by a ␤-galactosidase-neomycin cassette. In the mutant allele, ␤-galactosidase expression is under the control of the NRF-1 promoter. Embryos homozygous for NRF-1 disruption die between embryonic days 3.5 and 6.5. ␤-Galactosidase staining was observed in growing oocytes and in 2.5-and 3.5-day-old embryos, demonstrating that the NRF-1 gene is expressed during oogenesis and during early stages of embryogenesis. Moreover, the embryonic expression of NRF-1 did not result from maternal carryover. While most isolated wild-type and NRF-1 ؉/؊ blastocysts can develop further in vitro, the NRF-1 ؊/؊ blastocysts lack this ability despite their normal morphology. Interestingly, a fraction of the blastocysts from heterozygous matings had reduced staining intensity with rhodamine 123 and NRF-1 ؊/؊ blastocysts had markedly reduced levels of mitochondrial DNA (mtDNA). The depletion of mtDNA did not coincide with nuclear DNA fragmentation, indicating that mtDNA loss was not associated with increased apoptosis. These results are consistent with a specific requirement for NRF-1 in the maintenance of mtDNA and respiratory chain function during early embryogenesis.The electron transport and oxidative phosphorylation system in mammalian mitochondria requires contributions from both the nuclear and the mitochondrial genetic systems. The mitochondrial DNA encodes 13 respiratory subunits, as well as the 22 tRNAs and 2 rRNAs required for their mitochondrial translation. However, most respiratory proteins and all of the gene products required for mitochondrial DNA (mtDNA) replication and transcription are nucleus encoded (reviewed in references 39 and 42). Nuclear respiratory factor 1 (NRF-1) was identified as a nuclear transcription factor that transactivates the promoters of a number of mitochondrion-related genes in vitro (7,10,11,48). These include respiratory subunits, the rate-limiting heme biosynthetic enzyme, and factors involved in the replication and transcription of mtDNA (reviewed in reference 39). Among the most intriguing is TFAM, a nucleus-encoded transcription factor that acts on bidirectional promoters within the mitochondrial D-loop regulatory region (12). TFAM was recently shown to be essential for mitochondrial biogenesis during embryonic development (29) and for normal function of the heart (50). Moreover, NRF-1 is involved in the transcriptional control of mitochondrial biogenesis during adaptive thermogenesis through its interaction with the cold-inducible coactivator PGC-1 (53).In addition to its proposed role in respiratory chain expression, ...