HET/SAF-B overexpression causes growth arrest and multinuclearity and is associated with aneuploidy in human breast cancer

HET/SAF-B was originally cloned as a nuclear matrix protein that bound to m atrix attachment regions and as a transcriptional repressor of the small he at shock protein hsp27, In addition, we have found recently that HET/SAF-B is also a corepressor of estrogen receptor activity, Estrogen receptor has a very well-described role in breast cancer, and aberrant expression of nuc lear matrix and heat shock proteins has also been implicated in breast tumo rigenesis, Therefore, we asked whether HET/SAF-B itself could be important in breast cancer. Toward this goal we examined its expression in breast can cer cell lines and asked whether HET/SAF-B can affect breast cancer cell pr oliferation. Finally, we studied HET/SAF-B expression in clinical breast ca ncer samples. HET/SAF-B protein and mRNA were detected at varying levels in all of the ei ght breast cancer cell lines examined. Using a number of different approach es to modulate the level of HET/SAF-B protein in the cell, we found that HE T/SAF-B levels are inversely correlated with cell proliferation. In additio n, transfection of HET/SAF-B fused to the green fluorescent protein led to the formation of multinucleated cells not observed in cells transfected wit h green fluorescent protein alone, suggesting that this effect is a direct result of HET/SAF-B overexpression, Western blot analysis of HET/SAF-B in 6 1 human breast tumors revealed widely varying levels of HET/SAF-B expressio n, with some tumors (16%) lacking any detectable HET/SAF-B, Statistical ana lysis showed that high HET/SAF-B expression in these tumors was associated with low S-phase fraction and with aneuploidy, consistent with our results: from transfection experiments in tissue culture cells. We conclude that HE T/SAF-B plays an important role in breast cancer, and we discuss possible m echanisms of the involvement of HET/SAF-B in cell proliferation and divisio n.