Expression and Relevance of TRPS-1: A New GATA Transcription Factor in Breast Cancer

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.

Frequent MYC coamplification and DNA hypomethylation of multiple genes on 8q in 8p11-p12-amplified breast carcinomas

“…In breast tumors, TRPS1 expression is associated with ER, PgR, GATA3, HER2/ neu expression and favorable clinical outcome. 40, 41 Elevated NDRG1 protein levels have been associated with shorter disease-free and overall survival, cell differentiation and breast cancer progression. 42, 43, 44 In contrast, Han et al 45 demonstrated that NDRG1 methylation in breast cancer is associated with a more aggressive phenotype.…”

The Role of Tricho-Rhino-Phalangeal Syndrome (TRPS) 1 in Apoptosis during Embryonic Development and Tumor Progression

“…A quantitative immunohistochemistry (qIHC) approach found that TRPS1 protein expression in breast cancers above a certain threshold was correlated with markedly improved overall survival [20]. Trps1 is a target gene of miR-221/222 in luminally originated breast cancer cells counteracting EMT that restrains tumor cells from metastasis [19].…”

“…Subsequently, Trps1 was identified to be the most prevalently expressed gene in breast tumors [18]. Collective evidence shows that Trps1 may play a protective role in preventing tumor growth, invasion, and metastasis by promoting apoptosis and counteracting epithelial-mesenchymal transitions [3,19,20]. Recently, it has been reported that patients with mutations in the TRPS1 gene have increased susceptibility to tumorigenesis [21].…”

Transcriptomic analysis reveals key regulators of mammogenesis and the pregnancy-lactation cycle

“…Trps1 is a critical regulator of mesenchymal-to-epithelial cell transition [82]. Studies on renal tubule epithelial differentiation and the roles of Trps1 in other tissues pave the way for elucidating a potential role for Trps1 in mammary gland development [8284].…”