| Full description or Abstract | Toggle abstract view Loss of function of BRCA1 caused by inherited mutation and tissue-specific
somatic mutation leads to breast and ovarian cancer. Nearly all
BRCA1 germ-line mutations involve truncation or loss of the C-terminal
BRCT transcriptional activation domain, suggesting that transcriptional
regulation is a critical function of the wild-type gene. The purpose
of this project was to determine whether there is a link between
the role of BRCA1 in transcriptional regulation and its role in
tumor suppression. We developed a cell line (in which BRCA1 can
be induced) and used microarray analysis to compare transcription
profiles of epithelial cells with low endogenous levels of BRCA1
vs. transcription profiles of cells with 2-4-fold higher induced
levels of expression of BRCA1. At these levels of expression,
BRCA1 did not induce apoptosis. Undirected cluster analysis of
six paired experiments revealed 373 genes, the expression of which
was altered significantly and consistently by BRCA1 induction.
Expression of 62 genes was altered more than 2-fold. BRCA1-regulated
genes associated with breast tumorigenesis included the estrogen-responsive
genes MYC and cyclin D1, which are overexpressed in many breast
tumors; STAT1 and JAK1, key components of the cytokine signal
transduction pathway; the extracellular matrix protein laminin
3A; ID4, an inhibitor of DNA-binding transcriptional activators,
which in turn negatively regulates BRCA1 expression; and the prohormone
stanniocalcin, expression of which is lost in breast tumor cells.
Coordinated expression of BRCA1 with ID4 and with stanniocalcin
was confirmed in primary breast and ovarian tumors. |
| Keywords & MeSH headings | Neoplastic,Breast Neoplasms,Mutation,P.H.S.,Transfection,Cell Transformation,Human,Support,Complementary/genetics,Epithelial Cells/cytology/physiology,analogs & derivatives,Genes,genetics,BRCA1,Kidney,Cell Division/genetics,Breast/cytology/physiology,Cell Line,DNA,Female,pharmacology,Gene Expression Regulation/drug effects,Ovarian Neoplasms/genetics,Molecular,Kinetics,Ecdysterone,Gene Expression Regulation,Cloning |