Abstract
BackgroundThe Dachshund homolog 2 (DACH2) gene has been implicated in development of the female genital tract in mouse models and premature ovarian failure syndrome, but to date, its expression in human normal and cancerous tissue remains unexplored. Using the Human Protein Atlas as a tool for cancer biomarker discovery, DACH2 protein was found to be differentially expressed in epithelial ovarian cancer (EOC). Here, the expression and prognostic significance of DACH2 was further evaluated in ovarian cancer cell lines and human EOC samples.MethodsImmunohistochemical expression of DACH2 was examined in tissue microarrays with 143 incident EOC cases from two prospective, population-based cohorts, including a subset of benign-appearing fallopian tubes (n = 32). A nuclear score (NS), i.e. multiplier of staining fraction and intensity, was calculated. For survival analyses, cases were dichotomized into low (NS < = 3) and high (NS > 3) using classification and regression tree analysis. Kaplan Meier analysis and Cox proportional hazards modelling were used to assess the impact of DACH2 expression on survival. DACH2 expression was analysed in the cisplatin sensitive ovarian cancer cell line A2780 and its cisplatin resistant derivative A2780-Cp70. The specificity of the DACH2 antibody was tested using siRNA-mediated silencing of DACH2 in A2780-Cp70 cells.ResultsDACH2 expression was considerably higher in the cisplatin resistant A2780-Cp70 cells compared to the cisplatin-sensitive A2780 cells. While present in all sampled fallopian tubes, DACH2 expression ranged from negative to strong in EOC. In EOC, DACH2 expression correlated with several proteins involved in DNA integrity and repair, and proliferation. DACH2 expression was significantly higher in carcinoma of the serous subtype compared to non-serous carcinoma. In the full cohort, high DACH2 expression was significantly associated with poor prognosis in univariable analysis, and in carcinoma of the serous subtype, DACH2 remained an independent factor of poor prognosis.ConclusionsThis study provides a first demonstration of DACH2 protein being expressed in human fallopian tubes and EOC, with the highest expression in serous carcinoma where DACH2 was found to be an independent biomarker of poor prognosis. Future research should expand on the role of DACH2 in ovarian carcinogenesis and chemotherapy resistance.
Highlights
The Dachshund homolog 2 (DACH2) gene has been implicated in development of the female genital tract in mouse models and premature ovarian failure syndrome, but to date, its expression in human normal and cancerous tissue remains unexplored
IHC performed on formalin fixed, paraffin embedded siRNA transfected A2780/Cp70 cells revealed a marked decrease in immunoreactivity in the DACH2 knockdown cells compared to controls as visualized by IHC on cell pellets (Figure 1D)
Images representing different patterns of expression in tubal epithelium and epithelial ovarian cancer (EOC) are shown in Figure 2 A-H, whereby A-B represent tubal epithelium, C-E tumours with a nuclear score (NS) < = 3 and F-H tumours with a NS > 3
Summary
The Dachshund homolog 2 (DACH2) gene has been implicated in development of the female genital tract in mouse models and premature ovarian failure syndrome, but to date, its expression in human normal and cancerous tissue remains unexplored. Using the Human Protein Atlas as a tool for cancer biomarker discovery, DACH2 protein was found to be differentially expressed in epithelial ovarian cancer (EOC). Using the Human Protein Atlas http://www.proteinatlas.org as a tool for antibody based biomarker discovery [3,4], the Dachshund 2 (DACH2) protein was identified as being differentially expressed among EOC samples, ranging from negative to strong nuclear staining. Based on this observation, we hypothesized that DACH2 might be involved in ovarian carcinogenesis and, a putative prognostic and treatment predictive biomarker in EOC. The DACH2 gene has been implicated in premature ovarian failure (POF) syndrome [12,13], indicating that alterations of the human DACH2 protein may constitute a risk-factor for POF by altering the correct process of ovarian follicle differentiation [13]
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