Original contributionGATA-3 and FOXA1 expression is useful to differentiate breast carcinoma from other carcinomas☆
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.
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Materials and methods
The study was approved by the institutional review board of the Emory University Hospital. Tissue microarrays (TMAs) with duplicates of 1-mm-diameter tissue cores composed of normal breast tissue and breast carcinomas, including ER+/Her2−, Her2+, and triple-negative carcinomas, were selected for study. TMAs of 10 other common carcinomas, including 100 hepatocellular, 81 colonic, 28 pancreatic, 31 gastric, 27 endometrial (endometrioid), 27 lung, 48 prostatic, 48 renal cell, 79 urothelial, and 27
GATA-3 staining shows high specificity in breast and urothelial carcinoma
Nuclear staining of GATA-3 was evaluated in all TMAs. Among the breast carcinomas stained with GATA-3, 115 (96.6%) of the 119 ER+ carcinomas, 66 (82.2%) of 80 Her2+ carcinomas, and 11 (21.6%) of 51 triple-negative carcinomas were positive (Fig. 1, Fig. 2, Table). Fifty-six (70.9%) of 79 urothelial carcinomas were positive for GATA-3 staining (Fig. 3, Table). None of the remaining tumors were immunoreactive for GATA-3 staining. The overall sensitivity and specificity of GATA-3 staining for all
Discussion
Differentiating carcinomas of unknown primary origin is a problematic issue pathologists often face. Breast carcinomas can metastasize to almost any organ, and the breast is not an uncommon site of metastasis. One should be especially cautious when diagnosing high-grade carcinoma of the breast as a primary carcinoma without an in situ carcinoma component. For example, ovarian high-grade serous carcinoma can have its first clinical manifestation as a breast mass [17]. Commonly used breast
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The authors have no disclosures of conflict of interest and funding support for this manuscript.