Androgen Receptor driven gene score identifies tumors with Epithelial to Mesenchymal Transition features in triple negative breast cancer

Abstract

Background: Androgen receptor (AR) is considered marker associated with better prognosis within hormone receptor positive tumors. Its role in triple negative tumors however is controversial showing both better and worse prognosis and different methods are used for identification of AR driven tumors. Conflicting results could be due to intrinsic molecular differences or scoring method for AR positivity. We attempted to develop an AR driven gene score and examined its utility in subtypes of breast cancer (BC). Methods: A bioinformatic pipeline was constructed and applied on publicly available microarray data sets obtained from AR positive BC cell lines treated with dihydrotestosterone (DHT). Expression levels of genes identified through the pipeline along with set of epithelial mesenchymal transition (EMT) markers, proliferation associated genes and enzymes involved in intracrinal androgen metabolism was evaluated in a cohort of Indian Breast cancer patients. Tumors were divided into AR high and low based on the gene score and association with clinical parameters, circulating androgens, disease free survival, proliferation and EMT markers were examined, all results were further validated in external public datasets. Results: AR driven gene score was calculated as average expression of the 6 genes selected through bioinformatic analysis. 53% (133/249) tumors were classified as AR high by the gene score and had significantly better clinical parameters such as higher age, smaller tumor size, lower grade and lower proliferation. Tumors with high AR driven gene score had significantly better disease-free survival (mean survival time of 86.13 vs 72.69 months, log rank p=0.032) when compared to the AR low tumors. A subset analysis within TNBC (N=66) showed 36% (24/66) were AR high and had significantly higher expression of EMT markers (p=0.024). Though circulating levels of total testosterone was not different between the groups, intratumoral levels of 5 alfa reductase (SRD5A1) was significantly high in tumors with high AR driven score. Conclusion: Role of AR in breast cancer is debatable and difficult to decipher with protein detection alone. Our results support the context dependent function of AR in driving better prognosis, while identifying its role in driving EMT within TNBC tumors.

Differential role of glucocorticoid receptor based on its cell type specific expression on tumor cells and infiltrating lymphocytes

“…Differentially expressed genes (DEGs) between the control and treatment groups were filtered based on a significant p-value ( p <0.05). Subsequently, the prioritization of genes followed a previously established methodology, incorporating features such as protein interaction network, graph parameters, and semantic similarity, to elucidate key candidates with potential functional significance [ 24 ].…”

Comprehensive molecular interaction map of TGFβ induced epithelial to mesenchymal transition in breast cancer

“…Additionally, TGFβ signalling is also observed to regulate several proinvasive genes (IL-8, IL-17, IL-11), cell cycle regulators (Cylin G2, p21, p27, p15, p53, p63) and stemness markers (CD24, CD44) in both SMADdependent and independent pathways. Recent studies have revealed a positive correlation between EMT and Androgen Receptor (AR) signalling influenced by ER signalling, specifically within the Triple-Negative Breast Cancer (TNBC) subtype 131 . Consequently, the induction of EMT in breast cancer cell lines by TGFβ and the cross-regulation observed underscores the distinct molecular composition of TNBC.…”