Alteration in the Nuclear Structure of Breast Cancer Cells in Response to ECM Signaling

摘要

Eukaryotic chromosomal DNA is folded into topologically independent loop domains by making a periodic attachment at the nuclear matrix. Genomic sequences at these bases of the loops are called matrix attachment regions (MARs), and proteins that specifically bind to MARs may be important for modulating DNA organization and cell function. Whether higher order chromosomal organization is changed due to cell transformation is not well understood. We have previously identified a MAR binding protein of 1 14kDa from malignant breast carcinomas. The p114 MAR-binding activity was found to be attributed to two separate proteins, poly(ADP-ribose) polymerase (PARP) and SAF-A. The activity was detected in all human breast tumor specimens but was undetectable in normal breast or benign lesions. PARP-depleted breast cancer MDA-MB-231 cells lost the ability to grow in soft agar in an anchorage-independent fashion, showed reduced invasive activity in vitro, and exhibited changes in cell morphology on Matrigel. We compared gene expression profiles of control MDA-MB- 231 cells with PARP-deleted MDA-MB-231 cells and found many genes related to DNA/RNA binding, cell cycle regulation, chromosome assembly and redox regulation to be up-or down-regulated upon PARP deletion. Our data suggest that studies on the role of MAR- binding proteins will advance our knowledge on the mechanisms underlying breast tumor progression.