Department of Breast Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA.
Horm Cancer. 2011 Apr;2(2):132-43. doi: 10.1007/s12672-011-0067-5.
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.
GATA 转录因子家族成员在许多组织类型的分化中发挥着关键作用。例如，已经发现 GATA-3 与雌激素受体 α（ER）表达高度相关，并且正在成为乳腺导管上皮细胞分化的“主调控因子”之一。最近，我们发现另一种在乳腺癌中高度普遍存在的 GATA 家族成员，称为 trichorhinophalangeal 综合征-1 基因（TRPS-1）。使用定量免疫组织化学（qIHC）方法，我们发现 TRPS-1 与 ER、PR、GATA-3 以及 HER2 表达显著相关。然而，还发现 TRPS-1 在很大比例的 ER（-）导管上皮性乳腺癌（BC）中表达，这表明它可能在乳腺上皮细胞分化途径中的某个点作为导管上皮细胞特异性转录因子调节细胞命运。与该假设一致，我们发现使用 qIHC 在 BC 中超过一定阈值的 TRPS-1 蛋白表达与显著改善的总生存期相关。Cox 比例风险分析发现，TRPS-1 和 ER 表达均超过临界阈值同样预测生存改善。因此，TRPS-1 可能是 BC 中一种强大的新的阳性预后标志物，需要进一步的 IHC 研究以及对其在乳腺导管上皮细胞分化中的分子功能的检查。在这方面，关于 TRPS-1 在其他组织如肾脏后肾间充质细胞、柱状软骨细胞和成骨细胞中从间充质前体细胞分化中的作用的数据在小鼠模型中可能是有用的。事实上，这些研究发现 TRPS-1 是间充质向上皮细胞转化的关键调节剂。在乳腺中，TRPS-1 在人、鼠和大鼠导管上皮细胞中的限制表达表明，它在乳腺导管腔前体/干细胞分化过程中也可能发挥类似作用。我们提出了一个 TRPS-1 作用的模型，其中它可能在上皮细胞祖细胞或乳腺干细胞的早期阶段在上游作用于 GATA-3 和 ER，在乳腺发育过程中还帮助防止 ER（+）BC 细胞逆转回间充质样细胞。该模型预测，TRPS-1 表达低或无的 BC 固有地分化程度较低，侵袭性更强，预后较差。
