GATA-3 and FOXA1 expression is useful to differentiate breast carcinoma from other carcinomas

Summary

GATA-3, a member of the GATA family of zinc-finger DNA binding proteins, and FOXA1, a member of the forkhead transcription factor family, are both associated with estrogen receptor expression. Both GATA-3 and FOXA1 are useful markers for breast carcinoma, but their expression in the different breast cancer subtypes and other neoplasms has not been thoroughly evaluated. We examined the expression of GATA-3 and FOXA1 in estrogen receptor–positive, Her2/neu–positive, and triple-negative breast carcinomas as well as in 10 other common carcinomas, including hepatocellular, colonic, pancreatic, gastric, endometrial (endometrioid), lung, prostatic, renal cell, urothelial, and ovarian serous carcinomas. Primary and metastatic melanomas and mesotheliomas were also evaluated. GATA-3 and FOXA1 staining of estrogen receptor–positive breast carcinomas was seen in 96.6% and 96.2%, respectively. In triple-negative breast carcinomas, GATA-3 and FOXA1 staining was seen in 21.6% and 15.9%, respectively. Among the other tumors, GATA-3 staining was only seen in urothelial carcinoma (70.9%) and FOXA1 staining was only seen in prostatic (87.5%), urothelial (5.1%) carcinomas, and mesotheliomas (40.0%). In conclusion, GATA-3 and FOXA1 are excellent breast carcinoma markers; however, their utility is limited in the triple-negative subtype. The utility of FOXA1 in diagnosing prostatic carcinoma and mesothelioma warrants further investigation.

Introduction

It is often challenging in the daily practice of pathology to diagnose metastatic carcinomas of unknown primary. Metastatic carcinomas, especially adenocarcinomas, commonly share overlapping morphology. Breast carcinomas in particular frequently metastasize to other organs and the breast may also be a site of metastasis. Immunohistochemical studies play an important role in the work-up of such tumors. However, biomarkers such as mammaglobin, gross cystic disease fluid protein and estrogen receptor (ER), which are often used in the diagnosis of breast carcinoma, are limited by their low sensitivity and specificity [1], [2].

GATA-3, a member of the GATA family of zinc-finger DNA binding proteins, has been associated with ER expression in breast carcinoma, especially in the luminal subtype [3], [4]. GATA-3 is necessary for the regulation of mammary gland morphogenesis and luminal cell differentiation [5]. Recent studies have shown its utility in the diagnosis of breast and urothelial carcinomas [1], [6], [7], but few studies have evaluated its expression in different subtypes of breast cancers, especially Her2+ and triple-negative breast carcinoma. In addition, GATA-3 is positive in both breast and urothelial cell carcinoma. Thus additional markers are needed to differentiate these two carcinomas.

FOXA1 (Forkhead-box protein A1) is a member of the forkhead transcription factor family, which encompasses a wide array of proteins involved in numerous pathways [8]. FOXA1 has been identified as a key element in the ER-associated regulatory pathway [9], and down-regulation of FOXA1 impairs ER association with its binding sites [10], [11]. FOXA1 expression has been correlated with the luminal subtype in breast carcinoma [12] and associated with better prognosis [13]. FOXA factors also play an important role in the organogenesis of numerous organs, including the prostate [14], and FOXA1 expression is integral to androgen receptor transactivation [15].

In this study, we investigated the expression of GATA-3 and FOXA1 in different subtypes of breast carcinomas and in other malignant neoplasms to evaluate their utility in daily surgical pathology diagnosis.