Guan Lab

Department of Computational Medicine & Bioinformatics
Sun, 07/19/2015 - 23:10 -- gyuanfan
TitleComputational Inferences of the Functions of Alternative/Non-Canonical Splice Isoforms Specific to HER2+/ER-/PR- Breast Cancers, a Chromosome 17 C-HPP Study.
Publication TypeJournal Article
Year of Publication2015
AuthorsMenon R, Panwar B, Eksi R, Kleer C, Guan Y, Omenn GS
JournalJ Proteome Res
Date Published2015 Jul 6
ISSN1535-3907
Abstract

This study was conducted as a part of the Chromosome-Centric Human Proteome Project (C-HPP) of the Human Proteome Organization. The main objective is to identify and evaluate functionality of a set of specific non-canonical isoforms expressed in HER2-neu positive, Estrogen receptor negative (ER-), and Progesterone receptor negative (PR-) breast cancers (HER2+/ER-/PR- BC), an aggressive subtype of breast cancers (BC) that cause significant morbidity and mortality. We identified 11 alternative splice isoforms that were differentially expressed in HER2+/ER-/PR- BC compared to normal mammary, triple negative breast cancer and triple positive breast cancer tissues (HER2+/ER+/PR+). We used a stringent criterion that differentially expressed non-canonical isoforms (adjusted p value < 0.05) have to be expressed in all replicates of HER2+/ER-/PR- BC samples and the trend in differential expression (up or down) is same in all comparisons. Of the 11 protein isoforms, 6 were over-expressed in HER2+/ER-/PR- BC. We explored possible functional roles of these 6 proteins using several complementary computational tools. Biological processes including cell cycle events and glycolysis were linked to 4 of these proteins. For example, glycolysis was the top ranking functional process for DMXL2 isoform3, with a fold change of 27 compared to just 2 for the canonical protein. No previous reports link DMXL2 with any metabolic processes; the canonical protein is known to participate in signaling pathways. Our results clearly indicate distinct functions for the 6 over-expressed alternative splice isoforms and these functions could be specific to HER2+/ER-/PR- tumor progression. Further detailed analysis is warranted as these proteins could be explored as potential biomarkers and therapeutic targets for HER2+/ER-/PR- BC patients.

DOI10.1021/acs.jproteome.5b00498
Alternate JournalJ. Proteome Res.
PubMed ID26147891