Abstract P3-10-41: Quantitative Immunohistochemical Analysis and Prognostic Significance of TRPS-1, a New GATA Transcription Factor Family Member, in Breast Cancer
Department of Breast Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA. Hormones and Cancer
(Impact Factor: 0.02).
02/2010; 1(1):21-33. DOI: 10.1007/s12672-010-0008-8
The trichorhinophalangeal syndrome 1 (TRPS-1) gene is a novel GATA transcription factor family member. Previously, using a gene expression profiling and immunohistochemistry (IHC) screen, we identified TRPS-1 as a highly prevalent gene in breast cancer (BC), expressed in >90% of estrogen receptor alpha (ERα)(+) and ERα(-) BC subtypes. TRPS-1 was also shown to be expressed in prostate cancer where it was shown to play a proapoptotic function during androgen withdrawal possibly through regulating antioxidant metabolism. The role of TRPS-1 and its prognostic significance in hormone-dependent and hormone-independent BC however is not known. In this study, we developed a new quantitative IHC (qIHC) method to further study TRPS-1 as a marker and possible prognostic indicator in BC. By using this method, a quantitative parameter for TRPS-1 expression called a quick score (QS) was derived from the measured labeling index and mean optical density after IHC and applied to a set of 152 stage II/III BC patients from 1993 to 2006 who did not receive preoperative chemotherapy. Associations between QS and tumor characteristics were evaluated using the Kruskal-Wallis test. A wide range of TRPS-1 QS was found among the sample set with higher TRPS-1 QS significantly associated with tumor ERα (p = 0.023 for QS and p = 0.028 for Allred score), progesterone receptor (p = 0.009), and GATA-3 (p < 0.0001). TRPS-1 QS was also positively associated with HER2 status (p = 0.026). Further analysis of different ductal structures in ten BC cases revealed that TRPS-1 expression was expressed at low levels in the remaining normal ducts and in areas of usual ductal hyperplasia but showed marked increase in expression in ductal carcinoma in situ and invasive carcinoma lesions in the tissue. An analysis of TRPS-1 expression in association with overall survival in the 152 stage II/III sample set also revealed that TRPS-1 QS (≥4.0) was significantly associated with improved survival (p = 0.0165). Patients with TRPS-1 QS <4 had a hazard ratio of 2 (p = 0.019) after univariate Cox proportional hazards analysis. In summary, this new qIHC approach was found to reveal critical differences in TRPS-1 expression in primary BC samples and found that it is a promising prognostic marker that should be further evaluated as a possible tumor suppressor gene facilitating improved survival in different subtypes of BC.
Available from: PubMed Central
- "As mentioned before, TRPS1 gene in human has been found to be overexpressed in breast cancer, expressed in more than 90% estrogen receptor α (ERα) positive and negative breast cancer subtype . The gene is localised on human chromosome 8q23–24.1, "
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ABSTRACT: Breast cancer is a heterogeneous disease consisting of different subtypes. Trichorhinophalangeal syndrome type 1 (TRPS1) gene, a GATA-type transcription factor, has been found to be highly expressed in breast cancer. Epithelial-to-mesenchymal transition (EMT) is known to play an important role in tumour invasion and metastasis. Our objective was to elucidate the different roles and clinical relevance of TRPS1 in different estrogen receptor (ER) expression subtypes of breast cancer.
An immunohistochemical study was performed. The correlation between clinicopathological features and other biomarker profiles were analysed statistically.
TRPS1 expression was correlated with the patients’ age (P = 0.017). It was positively related with ERα (P < 0.001), progesterone receptor (PR) (P < 0.001) and ERβ (P = 0.001) status, but negatively associated with Ki67 (P = 0.002) and HER2 (P = 0.025) status. In ERα-positive breast cancer, TRPS1 expression was positively associated with the expression of E-cadherin (P < 0.001), β-catenin(P = 0.001), ERβ (P = 0.03), and p53 (P = 0.002) status, while in ERα-negative breast cancer, TRPS1 expression was correlated with slug (P = 0.004), vimentin (P = 0.003), smooth muscle actin (SMA) (P = 0.031), and IMP3 (P = 0.005) expression.
Based on our findings, we conclude that TRPS1 is positively associated with E-cadherin and β-catenin status in ERα-positive breast cancer cells, while it is also significantly associated with mesenchymal markers of EMT in ERα-negative breast cancer cells. TRPS1 can be a prognostic marker depending on the type of breast cancer.
The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/8686515681264281
Available from: Igor C. Almeida
- "Immunohistochemistry was performed as previously described (16). Briefly, 5-μm paraffin-fixed tissue sections were deparaffinized in xylene and rehydrated through using a gradient of alcohol (100, 95 to 80%, Sigma, St. Louis, MO). "
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ABSTRACT: Bioinformatic tools and databases for glycobiology and glycomics research are playing increasingly important roles in functional studies. However, to verify hypotheses generated by computational glycomics with empirical functional assays is only an emerging field. In this study, we predicted glycan epitopes expressed by a cancer-derived mucin, MUC1, by computational glycomics. MUC1 is expressed by tumor cells with a deficiency in glycosylation. Although numerous diagnostic reagents and cancer vaccines have been designed based on abnormally glycosylated MUC1 sequences, the glycan and peptide sequences responsible for immune responses in vivo are poorly understood. The immunogenicity of synthetic MUC1 glycopeptides bearing Tn or sialyl-Tn antigens have been studied in mouse models, while authentic glyco-epitopes expressed by tumor cells remain unclear. To examine the immunogenicity of authentic cancer derived MUC1 glyco-epitopes, we expressed membrane bound forms of MUC1 tandem repeats in Jurkat, a mutant cancer cell line deficient of mucin-type core-1 β1-3 galactosyltransferase activity, and immunized mice with cancer cells expressing authentic MUC1 glyco-epitopes. Antibody responses to individual glyco-epitopes were determined by chemically synthesized candidate MUC1 glycopeptides predicted through computational glycomics. Monoclonal antibodies can be generated toward chemically synthesized glycopeptide sequences. With RPAPGS(Tn)TAPPAHG as an example, a monoclonal antibody 16A, showed 25-fold higher binding to glycosylated peptide (EC50=9.278±1.059 ng/ml) compared to its non-glycosylated form (EC50=247.3±16.29 ng/ml) as measured by ELISA experiments with plate-bound peptides. A library of monoclonal antibodies toward authentic MUC1 glycopeptide epitopes may be a valuable tool for studying glycan and peptide sequences in cancer, as well as reagents for diagnosis and therapy.
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ABSTRACT: GATA transcription factor family members have been found to play a critical role in the differentiation of many tissue types. For example, GATA-3 has been found to be highly correlated with estrogen receptor α (ER) expression and is emerging as one of the "master regulators" in breast ductal epithelial cell differentiation. Recently, we discovered another GATA family member highly prevalent in breast cancer called the trichorhinophalangeal syndrome-1 gene (TRPS-1). Using a quantitative immunohistochemistry (qIHC) approach, we found that TRPS-1 was significantly correlated with ER, PR, GATA-3, as well as HER2 expression. However, TRPS-1 was also found to be expressed in a high proportion of ER(-) ductal epithelial breast cancers (BCs), indicating that it may act as a ductal epithelial cell-specific transcription factor regulating cell fate at some point in the epithelial cell differentiation pathway. In keeping with this hypothesis, we found that TRPS-1 protein expression in BC above a certain threshold using qIHC correlated with markedly improved overall survival. Cox proportional hazards analysis found that both TRPS-1 and ER expression above critical threshold equally predicted for improved survival. Thus, TRPS-1 may be a powerful new positive prognostic marker in BC, and further IHC studies, as well as examination of its molecular function in ductal epithelial cell differentiation in the breast, are warranted. In this regard, data on the role of TRPS-1 in the differentiation of cells from mesenchymal precursors in other tissues, such as kidney metanephric mesenchymal cells, columnar chondrocytes, and osteoblasts, in mouse models may be useful. Indeed, these studies have found that TRPS-1 is a critical regulator of mesenchymal-to-epithelial cell transition. In the mammary gland, the restricted expression of TRPS-1 in human, mouse, and rat ductal epithelial cells suggests that it may also play a similar role during ductal luminal progenitor/stem cell differentiation. We present a model of TRPS-1 action in which it may act upstream of GATA-3 and ER on an earlier ductal epithelial progenitor cell or mammary stem cell during mammary gland development and also helps prevent reversion of ER(+) BC cells back into mesenchymal-like cells. This model predicts that BCs with low or no TRPS-1 expression may inherently be much less differentiated and more aggressive tumors with less favorable prognosis.
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