Elsevier

Human Pathology

Volume 44, Issue 7, July 2013, Pages 1341-1349
Human Pathology

Original contribution
GATA3 expression in breast carcinoma: utility in triple-negative, sarcomatoid, and metastatic carcinomas,☆☆

https://doi.org/10.1016/j.humpath.2012.11.003Get rights and content

Summary

GATA3 plays an integral role in breast luminal cell differentiation and is implicated in breast cancer progression. GATA3 immunohistochemistry is a useful marker of breast cancer; however, its use in specific subtypes is unclear. Here, we evaluate GATA3 expression in 86 invasive ductal carcinomas including triple-negative, Her-2, and luminal subtypes, in addition to 13 metaplastic carcinomas and in 34 fibroepithelial neoplasms. In addition, we report GATA3 expression in matched primary and metastatic breast carcinomas in 30 patients with known estrogen receptor (ER), progesterone receptor (PR), and Her-2 status, including 5 with ER and/or PR loss from primary to metastasis. Tissue microarrays containing 5 to 10 cores per tumor were stained for GATA3, scored as follows: 0 (0-5%), 1+ (6%-25%), 2+ (26%-50%), 3+ (51%-75%), and 4+ (>75%). GATA3 labeling was seen in 67% (66/99) of primary ductal carcinomas including 43% of triple-negative and 54% of metaplastic carcinomas. In contrast, stromal GATA3 labeling was seen in only 1 fibroepithelial neoplasm. GATA3 labeling was seen in 90% (27/30) of primary breast carcinomas in the paired cohort, including 67% of triple-negative carcinomas. GATA3 labeling was overwhelmingly maintained in paired metastases. Notably, GATA3 was maintained in all “luminal loss” metastases, which showed ER and/or PR loss. In conclusion, GATA3 expression is maintained between matched primary and metastatic carcinomas including ER-negative cases. GATA3 can be particularly useful as a marker for metastatic breast carcinoma, especially triple-negative and metaplastic carcinomas, which lack specific markers of mammary origin. Finally, GATA3 labeling may help distinguish metaplastic carcinoma from malignant phyllodes tumors.

Introduction

GATA3 is a member of the GATA family of zinc-finger binding transcription factors that regulates the specification and differentiation of many tissue types [1], [2] including the breast [3], [4], [5], kidney [6], T cells [7], nervous system [8], and hair follicles [9]. Although GATA3 is expressed in a wide variety of tissues, the expression of transcription factors in many tissues is at low levels that are not detectable by immunohistochemistry (IHC). Immunohistochemical labeling for GATA3 in normal tissues is far more restricted, and GATA3 labeling has been demonstrated to be a highly specific marker for breast carcinomas [10], [11] and urothelial carcinomas [11], [12].

Although the high specificity of GATA3 expression in breast carcinoma has been well established, several key questions remain that impact the clinical use of IHC for GATA3. First, although multiple studies have suggested that GATA3 is more frequently expressed in estrogen receptor (ER)–positive tumors compared with ER-negative tumors [10], [13], [14], few studies have examined the expression of GATA3 in primary breast carcinomas (PBCs) subdivided by IHC surrogate profiles of molecular subtypes [15]. Specifically, expression of GATA3 in “triple-negative” (ER, progesterone receptor [PR], and Her-2 negative) breast carcinomas is most relevant because mammary origin of that subtype is most difficult to prove by IHC. Second, expression of GATA3 in metaplastic (sarcomatoid) carcinomas, which must be distinguished from other spindle cell malignancies in the breast, has not been assessed. Third, although the main clinical use of GATA3 IHC would be to establish the diagnosis of metastatic carcinoma, the expression of GATA3 in breast cancer metastases has not been well studied. Moreover, no study has compared the expression of GATA3 in metastatic breast carcinomas (MBCs) related to their matched primary carcinomas to determine if these results are concordant.

Here, we systematically evaluated GATA3 expression in 86 invasive ductal carcinomas subdivided by IHC-defined molecular subtypes, including triple-negative carcinomas (TNCs), Her-2 carcinomas, and luminal carcinomas. We evaluated GATA3 expression in 13 metaplastic (sarcomatoid) carcinomas and, for comparison, in 34 fibroepithelial neoplasms of the breast. Finally, we report the first study of GATA3 expression in matched primary and MBCs harvested at surgery or autopsy in 30 patients with known ER, PR, and Her-2 status, including 5 cases where ER and/or PR expression was lost from the primary to the metastasis.

Section snippets

Primary invasive ductal carcinomas

This study was approved by the institutional review board of the Johns Hopkins Medical Institutions. We evaluated a series of tissue microarrays (TMAs) constructed from archived paraffin tissue blocks of 86 primary invasive ductal carcinomas, as previously described [16]. Each TMA consisted of 99 cores measuring 1.4 mm in diameter. Five cores were taken per case to minimize sampling error, including 1 core per case containing benign lobules. The cases were subdivided by established IHC

Clinicopathologic characteristics

The cohort of 86 primary invasive ductal carcinomas consisted of 21 luminal A carcinomas, 7 luminal B carcinomas, 14 Her-2 carcinomas, and 44 TNCs. The 13 primary invasive metaplastic carcinomas were all triple negative for ER, PR, and Her-2; were intermediate to high grade; and contained spindled, squamous, chondroid, and/or osseous metaplastic components.

The clinicopathologic characteristics of the patients in the cohorts of paired PBCs and MBCs are seen in Table 1. In the cohort of

Discussion

The GATA family of zinc-finger binding transcription factors regulates the lineage determination and differentiation of many tissue types including the mammary gland [1]. GATA3 plays an integral role in the differentiation of breast luminal epithelial cells and in the morphogenesis of the normal breast [2], [3], [4], [5]. The expression of GATA3 in murine breast cancers models inhibits the transition from an epithelial to mesenchymal phenotype [27], [28] and the development of metastases [29],

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    Disclosures: The authors have no conflicts of interest to disclose.

    ☆☆

    Funding source: The study was supported by Johns Hopkins Hospital Breast Cancer Research Fund (A.C.M.).

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