Biology subjects

Rajarajan, S.

Publications and source records attributed to Rajarajan, S..

3 recordsLinked to original sources

bioRxiv2023

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

BackgroundAndrogen 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). MethodsA 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. ResultsAR 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. ConclusionRole 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.

cancer biology↗

bioRxiv2023

BRCA1 expression, its correlation with clinicopathological features and response to neoadjuvant chemotherapy in high grade serous ovarian cancer from an Indian centre

In high grade serous ovarian cancers (HG-SOC), BRCA1/2 mutations have been reported as the most predominant mutations by various studies. However, the non-mutational mechanisms of BRCA pathway inactivation in HG-SOC are unclear. We aimed to evaluate BRCA1 inactivation by estimating its expression along with its repressor in primary and neoadjuvant chemotherapy (NACT) treated HG-SOC tumors with known therapeutic response. The expression pattern of BRCA1 protein was evaluated by immunohistochemistry (IHC) in 119 cases of HG-SOC from a hospital cohort consisting of primary (N= 69) and NACT treated (N=50) tumors. Histological patterns (SET), stromal infiltration by lymphocytes (sTILs) and chemotherapy response score (CRS) were estimated by microscopic examination. Gene expression levels of BRCA1, and its repressor ID4 was estimated by qPCR. Association of BRCA1 protein and mRNA with clinicopathological features was studied. Relevance of the BRCA1/ID4 ratio was evaluated in tumors with different CRS. BRCA1 protein expression was observed in 12% of primary and 19% of NACT treated HG-SOC tumors. Moderate concordance was observed between BRCA1 protein and mRNA expression (AUC-0.677). High BRCA1 mRNA expression was significantly associated with more frequent SET pattern (p=0.024), higher sTILs density (p=0.042), increased mitosis (p=0.028). BRCA1 negative tumors showed higher expression of ID4 though not statistically significant. Higher BRCA1/ID4 ratio was associated with high sTILs density in primary (p=0.042) and NACT treated tumors (p=0.040). Our findings show the utility of BRCA1/ID4 ratio to predict neoadjuvant therapy response, which needs further evaluation in larger cohort with long term outcomes.

cancer biology↗

bioRxiv2022

Acquisition of hybrid E/M phenotype associated with increased migration, drug resistance and stemness is mediated by reduced miR-18a levels in ER-negative breast cancer

The complexity of the ER-negative subtype of breast cancer arises due to the heterogeneous nature of the disease rendering them more aggressive and this poses a challenge to effective treatment and eventually the prognosis of the patients. We have explored the miRNA regulation of altered molecular signatures and the effect on tumour progression in ER-negative breast cancer. Using breast tumour specimens, gene expression data from public datasets and in-vitro and in-vivo model systems we have shown that low-levels of miR-18a in ER-negative tumours drives enrichment of hybrid Epithelial/Mesenchymal (E/M) cells with luminal attributes. On inhibition of miR-18a in ER-negative breast cancer cell lines, the cells showed traits of increased migration, stemness and drug-resistance. miR-18a/low tumours were also associated with increased expression of genes associated with EMT, stemness, drug resistance and immune-suppression. Further analysis of the miR-18a targets pointed out at a possible HIF-1 mediated signalling in these tumours. HIF-1 inhibition reduced the enrichment of the hybrid E/M cells and decreased the migratory ability of miR-18a/low cells. Our study reports for the first time a dual role of miR-18a in breast cancer that is subtype specific based on hormone receptor expression and a novel association of low miR-18a levels and enrichment of hybrid E/M cells. The results highlight the possibility of stratifying the ER-negative disease into clinically relevant groups by analysing epigenetic signatures.

cancer biology↗