High level expression of differentially localized BAG-1 isoforms in some oestrogen receptor-positive human breast cancers

Sensitivity to oestrogens and apoptosis are critical determinants of the de velopment and progression of breast cancer and reflect closely linked pathw ays in breast epithelial cells. For example, induction of BCL-2 oncoprotein expression by oestrogen contributes to suppression of apoptosis and BCL-2 and oestrogen receptor (ER) are frequently co-expressed in tumours. BAG-1/H AP is a multifunctional protein which complexes with BCL-2 and steroid horm one receptors (including the ER), and can suppress apoptosis and influence steroid hormone-dependent transcription. Therefore, analysis of expression of BAG-1 in human breast cancer is of considerable interest. BAG-1 was read ily detected by immunostaining in normal breast epithelial cells and most E R-positive tumours, but was undetectable or weakly expressed in ER-negative tumours. BAG-1 positive cells showed a predominantly cytoplasmic or cytopl asmic plus nuclear distribution of staining, A correlation between ER and B AG-1 was also evident in breast cancer derived cell lines, as all lines exa mined with functional ER expression also expressed high levers of BAG-1. In addition to the prototypical 36 kDa BAG-1 isoform, breast cancer cells exp ressed higher molecular weight isoforms and, in contrast to BCL-2, BAG-1 ex pression was independent of oestrogens. BAG-1 isoforms were differentially localized to the nucleus or cytoplasm and this was also independent of oest rogens. These results demonstrate a close association between BAG-1 and fun ctional ER expression and suggest BAG-1 may be useful as a therapeutic targ et or prognostic marker in breast cancer. (C) 1999 Cancer Research Campaign .