Original contributionGATA3 expression in breast carcinoma: utility in triple-negative, sarcomatoid, and metastatic carcinomas☆,☆☆
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],
References (45)
- et al.
GATA-3 maintains the differentiation of the luminal cell fate in the mammary gland
Cell
(2006) - et al.
GATA-3 and the regulation of the mammary luminal cell fate
Curr Opin Cell Biol
(2008) - et al.
A study of immunohistochemical differential expression in pulmonary and mammary carcinomas
Mod Pathol
(2010) - et al.
The significance of GATA3 expression in breast cancer: a 10-year follow-up study
Hum Pathol
(2009) - et al.
Androgen receptor expression is usually maintained in initial surgically-resected breast cancer metastases, but often lost in terminal metastases found at autopsy
Hum Pathol
(2012) - et al.
GATA3 inhibits breast cancer metastasis through the reversal of epithelial-mesenchymal transition
J Biol Chem
(2010) - et al.
GATA-3 links tumor differentiation and dissemination in a luminal breast cancer model
Cancer Cell
(2008) - et al.
GATA-3 expression as a predictor of hormone response in breast cancer
J Am Coll Surg
(2005) - et al.
Higher levels of GATA3 predict better survival in women with breast cancer
Hum Pathol
(2010) - et al.
GATA-3 as a marker of hormone response in breast cancer
J Surg Res
(2009)
Clinicopathological analysis of GATA3-positive breast cancers with special reference to response to neoadjuvant chemotherapy
Ann Oncol
GATA transcription factors and cancer
Genes Cancer.
GATA3 in development and cancer differentiation: cells GATA have it!
J Cell Physiol
Gata-3 is an essential regulator of mammary-gland morphogenesis and luminal-cell differentiation
Nat Cell Biol
Pax2/8-regulated Gata3 expression is necessary for morphogenesis and guidance of the nephric duct in the developing kidney
Development
Transcription factor GATA-3 is required for development of the T-cell lineage
Nature
Gata3 loss leads to embryonic lethality due to noradrenaline deficiency of the sympathetic nervous system
Nat Genet
GATA-3: an unexpected regulator of cell lineage determination in skin
Genes Dev
Immunohistochemical evaluation of GATA3 expression in tumors and normal tissues: a useful immunomarker for breast and urothelial carcinomas
Am J Clin Pathol
Placental S100 (S100P) and GATA3: markers for transitional epithelium and urothelial carcinoma discovered by complementary DNA microarray
Am J Surg Pathol
Expression of FOXA1 and GATA-3 in breast cancer: the prognostic significance in hormone receptor-negative tumours
Breast Cancer Res
Heterogeneity for stem cell–related markers according to tumor subtype and histologic stage in breast cancer
Clin Cancer Res
Cited by (174)
Utility of TRPS-1 immunohistochemistry in diagnosis of metastatic breast carcinoma in cytology specimens
2022, Journal of the American Society of CytopathologyCitation Excerpt :Similarly, Cimino-Mathews et al10 found that GATA-3 reactivity was present in 67% of primary BCs and showed that GATA-3 reactivity was maintained in most cases of matched metastasis. Although GATA-3 outperformed other commonly used markers of breast differentiation, it might only stain one half of the metastatic TNBC.10,11 Although GATA-3 is highly expressed in BC and tightly correlated to ER expression, it is not specific.
Immunohistochemical Markers for Distinguishing Metastatic Breast Carcinoma from Other Common Malignancies: Update and Revisit
2022, Seminars in Diagnostic PathologyTRPS1, GATA3, and SOX10 expression in triple-negative breast carcinoma
2022, Human PathologyDiagnostic utility of PELP1 and GATA3 in primary and metastatic triple negative breast cancer
2022, Revista de Senologia y Patologia Mamaria
- ☆
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.).