Strong androgen receptor expression can aid in distinguishing GATA3+ metastases.

GATA3 is a transcription factor used clinically as a marker of breast or urothelial differentiation. A marker is yet needed to distinguish this in the case of the GATA3-positive tumor of unknown origin. We tested classical markers of breast differentiation and hormonal signaling to see which correlated strongest with GATA3 expression in breast cancer and thus which could help correctly identify breast origin in the case of the GATA3-positive tumor of unknown origin. GATA3, estrogen receptor, progesterone receptor, androgen receptor (AR), HER2, GCDFP15, and mammaglobin expression was intercorrelated in a histologically diverse 259-case breast cancer tissue microarray. We show herein a uniquely high level of correlation between GATA3 and AR expression (r=0.61; 95% confidence interval 0.52-0.68) that was strongest among lobular carcinomas (r=1; 95% confidence interval 0.73-1) and stronger than any other correlation studied. Separate AR staining of 10 metastatic GATA3+ carcinomas of urothelial origin and 13 metastatic GATA3+ carcinomas of breast origin showed that strong AR staining (>60% of tumor cells) has a sensitivity of 54% and a specificity of 100% for correctly distinguishing GATA3+ carcinoma of mammary origin from urothelial origin in the metastatic setting. Androgen receptor expression is strongly correlated with GATA3 in breast cancer, particularly in tumors with lobular morphology. Strong AR expression (>60% of tumor cells) is an excellent test to rule out urothelial carcinoma in the GATA3+ metastatic setting (specificity 100%) and will effectively identify breast origin in approximately 50% of cases.