DACH1: Its Role as a Classifier of Long Term Good Prognosis in Luminal Breast Cancer

Abstract

BackgroundOestrogen receptor (ER) positive (luminal) tumours account for the largest proportion of females with breast cancer. Theirs is a heterogeneous disease presenting clinical challenges in managing their treatment. Three main biological luminal groups have been identified but clinically these can be distilled into two prognostic groups in which Luminal A are accorded good prognosis and Luminal B correlate with poor prognosis. Further biomarkers are needed to attain classification consensus. Machine learning approaches like Artificial Neural Networks (ANNs) have been used for classification and identification of biomarkers in breast cancer using high throughput data. In this study, we have used an artificial neural network (ANN) approach to identify DACH1 as a candidate luminal marker and its role in predicting clinical outcome in breast cancer is assessed.Materials and methodsA reiterative ANN approach incorporating a network inferencing algorithm was used to identify ER-associated biomarkers in a publically available cDNA microarray dataset. DACH1 was identified in having a strong influence on ER associated markers and a positive association with ER. Its clinical relevance in predicting breast cancer specific survival was investigated by statistically assessing protein expression levels after immunohistochemistry in a series of unselected breast cancers, formatted as a tissue microarray.ResultsStrong nuclear DACH1 staining is more prevalent in tubular and lobular breast cancer. Its expression correlated with ER-alpha positive tumours expressing PgR, epithelial cytokeratins (CK)18/19 and ‘luminal-like’ markers of good prognosis including FOXA1 and RERG (p<0.05). DACH1 is increased in patients showing longer cancer specific survival and disease free interval and reduced metastasis formation (p<0.001). Nuclear DACH1 showed a negative association with markers of aggressive growth and poor prognosis.ConclusionNuclear DACH1 expression appears to be a Luminal A biomarker predictive of good prognosis, but is not independent of clinical stage, tumour size, NPI status or systemic therapy.

Dissecting DNA repair in adult high grade gliomas for patient stratification in the post-genomic era

“…Taken together the data suggest a complex role for APE1 in human tumours. We speculate that low APE1 in gliomas may promote a mutator phenotype where accelerated mutagenesis may promote aggressive cancers [40]. Similar to APE1 , low PTEN mRNA was also associated with poor survival in our study and is consistent with previous observations in gliomas [31, 32].…”

“…The aim of this was to identify genes that interacted with the key DNA repair genes identified earlier and to identify the most influential genes (hubs) in the DNA repair system. The advantage of the ANN approach was that it modelled using non-linear functions and was not constrained by reliance on linear mathematics [40]. We focussed this interactomic study on APE1 mRNA, NBN mRNA, PTEN mRNA, PMS2 mRNA and MGMT mRNA interactions.…”

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“…Our findings mirror those seen in other malignancies, e.g. FOXA1 upregulation confering a good prognosis on cancers with high expression [37, 38] and is a representative marker of luminal-type cancers [39], and are compatible with DeGraff et al given recent evidence of a dual role for up and down regulation of FOXA1 in cancer [40, 41]. …”

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“…Inactivation of DACH1 in human cancer tissues was observed by mechanisms of gene deletion, mutation, or promoter hypermethylation [21,23]. Clinically, a decreased expression of DACH1 in breast and endometrial cancer correlates with tumor progression, poor differentiation [23] and predicts a short survival [13,24,25]. In human lung adenocarcinoma, the transcription factor SIX1 is upregulated during preinvasive to invasive transition and that results in EMT and conferring a more malignant phenotype [26].…”