THE NRF-1/GABP/BRCA1 Transcriptional Network in Mammary Epithelial Differentiation
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Evidence indicates that the mammary epithelium is arranged in a hierarchy in which mature luminal and myoepithelial cells are derived from stem cells through a series of lineage-restricted intermediates. One of the more compelling hypotheses in breast cancer research is that transformation of a particular cell within the hierarchy will initiate a tumour with a specific molecular profile and clinical outcome. If this is true, valuable insight into tumourigenesis can be gained by investigating normal and malignant pathways of differentiation. A well-known tumour suppressor in breast cancer, BRCA1, plays a role in mammary epithelial differentiation. It has been proposed that haploinsufficiency or loss of BRCA1, either by germline mutation or sporadic downregulation, blocks differentiation producing a pool of genetically unstable mammary stem/progenitor cells that are prime targets for transformation. Thus, investigation of BRCA1 regulation and its role in differentiation are important to our understanding of breast cancer etiology. In this study, we determined that BRCA1 is at the end of a transcriptional network comprised of NRF-1 and GABP, a transcription factor comprised of two distinct subunits GABPalpha and GABPbeta. Decreased BRCA1 transcription in SK-BR-3 cells was found to be caused by aberrant activation of the GABPbeta promoter by an NRF-1 binding protein complex. We determined that the SWI/SNF family members BRG1, ARID1A and BAF155 may participate in the complex that activates GABPbeta transcription in conjunction with NRF-1. Examination of NRF-1, GABP and BRCA1 in 3D culture models suggests that mammary epithelial differentiation is biphasic with the transition between the phases being driven by changes in BRCA1 expression and localization. In the first phase, BRCA1 promotes differentiation in the nucleus, and in the second phase, BRCA1 is downregulated as a result of diminished GABP expression and relocated to an apical position, presumably to facilitate cell polarization. Following BRCA1 downregulation, NRF-1 and GABP levels increase indicating they are inducing oxidative phosphorylation in the second phase of differentiation. The involvement of NRF-1 and GABP in cellular respiration as well as differentiation through targets such as BRCA1 suggests that these proteins may integrate the cellular functions and mitochondrial metabolism required for mammary epithelial differentiation.