Oncometabolite profiling identifying estrogen-responsive genes in breast cancer.

Abstract

e13611 Background: Metabolomic profiling in breast cancer (BC) is an emerging avenue to identify clinically actionable biomarkers as well as targeted therapeutics. Altered metabolic pathways has been identified in BC. Studies have discovered an association between oncometabolite levels, DNA methylation and other epigenetic changes, with prognosis in BC. Changes in cancer cells metabolism may thus indicate disease aggressiveness and its response to therapy. Methods: An in-silico based oncometabolite profiling was performed in ER +ve and TNBC (ER-/PR-/Her2-) data sets using NCBO-GEO tools. . Inclusion criteria included studies on Human subjects, having at least 2 ER+ PR+ and TNBC samples. After manually filtering the top 250 most significant differentially expressed genes in all studies, those with clear metabolic functions as per the GO category were pooled together, which included both the overexpressed and downregulated genes. 15 unique genes were cherry-picked and taken for further analysis out of which six were downregulated, and nine were upregulated. The identified genes harbouring ERE in their upstream 1000bp region were further analysed to identify CpG islands. In addition, we also performed a Bio-Reader based Text Mining Tool to streamline Pubmed abstracts with the positive strings “oncometabolite,” “breast cancer,” “stem cells” “survival”. We also queried against negative strings “sequencing,” “mutations,” “infections,” “drug-resistance” to develop a list of highly focused abstracts. Results: Novel estrogen-regulated oncometabolite that were differentially expressed in ER+ve vs TNBC BC were identified. Further, we reinforced the fact that 4 out of 7 targets had upstream CpG islands within 1000bp n Both upregulated AMY2A, B3GNT5, PNPLA3 and 2HG whereas and downregulated genes in PLCD4, FBP1 and CA12 along with one target identified from the literature were selectively expressed in ER+ve BC. Conclusions: Our study has identified estrogen-responsive metabolic genes involved in BC. We are currently validating our results in a wet lab setup from breast cancer patient samples. Validated targets may be tested for therapeutic intervention in BC.