Loss of androgen receptor associated protein 70 (ARA70) expression in a subset of HER2-positive breast cancers

Co-transfection studies indicate that HER2 (erbB-2) overexpression results in the phosphorylation and enhanced transcriptional activity of the androge n receptor (AR). This amplification of AR action is further enhanced by the expression of ARA70, a putative co-activator with a predilection for the A R. Because androgens inhibit the growth of breast cancer cells whereas HER2 overexpression stimulates the growth of these cells, it seems possible tha t loss of expression of AR or ARA70 in some HER2 overexpressing tumors migh t confer a growth advantage to these cells. We examined ARA70 and AR expres sion in 20 HER2-positive (overexpressing) and 21 HER2-neggative cases of br east invasive ductal carcinoma (IDC) to determine the relationship between loss of ARA70 and/or AR with HER2 overexpression. Strong ARA70 immunostaini ng was observed in all normal and breast epithelial cells in fibrocystic ch ange and in in situ carcinoma present in the patient samples. Of the 41 cas es of IDC, focal or complete loss of ARA70 protein expression was observed in 46% of the cases, with 60% of HER2-positive versus 33% of HER2-negative cases showing loss. Loss of AR expression was observed in 60% of HER2-posit ive versus 43% of HER2-negative cases. Remarkably, only 20% of HER2-positiv e tumors expressed both AR and ARA70, while 43% of HER2-negative tumors exp ressed both of these elements of the AR signaling pathway. This trend is co nsistent with a possible clinical relevance of the potential crosstalk betw een the HER2 and AR signaling pathways. Western blot analysis for ARA70 exp ression performed on frozen breast biopsies of normal or malignant breast t issue from four patients revealed a 70 kDa immunoreactive band in all four normal tissue samples, with an additional 35 kDa band in two of the breast cancer samples and in human breast cancer MCF-7 cells. This may reflect abe rrant splicing in some breast cancers, leading to the emergence of the 35 k Da isoform.