Abstract
Breast and ovarian cancer susceptibility genes BRCA1 and PALB2 have enigmatic roles in cellular growth and mammalian development. While these genes are essential for growth during early developmental programs, inactivation later in adulthood results in increased growth and formation of tumors, leading to their designation as tumor suppressors. We performed genome‐wide analysis assessing their chromatin residence and gene expression responsiveness using high‐throughput sequencing in breast epithelial cells. We found an intimate association between BRCA1 and PALB2 chromatin residence and genes displaying high transcriptional activity. Moreover, our experiments revealed a critical role for BRCA1 and, to a smaller degree, PALB2 in transcriptional responsiveness to NF‐κB, a crucial mediator of growth and inflammatory response during development and cancer. Importantly, we also uncovered a vital role for BRCA1 and PALB2 in response to retinoic acid (RA), a growth inhibitory signal in breast cancer cells, which may constitute the basis for their tumor suppressor activity. Taken together, our results highlight an important role for these breast cancer proteins in the regulation of diverse growth regulatory pathways.
Synopsis
High‐throughput sequencing reveals chromatin‐binding sites of the breast cancer tumor suppressors BRCA1 and PALB2 and suggests transcription co‐regulatory roles at a subset of genes, including NF‐κB targets and retinoic acid‐responsive genes.
BRCA1 and PALB2 occupy transcriptional start sites and gene bodies of highly active genes in breast epithelial cells.
Inhibition of RNA polymerase II elongation abrogates BRCA1 and PALB2 chromatin residence.
BRCA1 and PALB2 are transcriptional co‐activators of a subset of NF‐κB‐regulated genes.
Depletion of BRCA1 and PALB2 diminishes retinoic acid responsiveness in breast cancer cells.
Two major tumor suppressors bind to and co‐regulate highly transcribed genes in breast epithelial cells, including NF‐κB targets and retinoic acid‐responsive genes.
