Distinct Splice Variants and Pathway Enrichment in the Cell-Line Models of Aggressive Human Breast Cancer Subtypes

This
study was conducted as a part of the Chromosome-Centric Human
Proteome Project (C-HPP) of the Human Proteome Organization. The United
States team of C-HPP is focused on characterizing the protein-coding
genes in chromosome 17. Despite its small size, chromosome 17 is rich
in protein-coding genes; it contains many cancer-associated genes,
including BRCA1, ERBB2, (Her2/neu), and TP53. The goal of this study
was to examine the splice variants expressed in three ERBB2 expressed
breast cancer cell-line models of hormone-receptor-negative breast
cancers by integrating RNA-Seq and proteomic mass spectrometry data.
The cell lines represent distinct phenotypic variations subtype: SKBR3
(ERBB2+ (overexpression)/ER–/PR–; adenocarcinoma), SUM190
(ERBB2+ (overexpression)/ER–/PR–; inflammatory breast
cancer), and SUM149 (ERBB2 (low expression) ER–/PR–;
inflammatory breast cancer). We identified more than one splice variant
for 1167 genes expressed in at least one of the three cancer cell
lines. We found multiple variants of genes that are in the signaling
pathways downstream of ERBB2 along with variants specific to one cancer
cell line compared with the other two cancer cell lines and with normal
mammary cells. The overall transcript profiles based on read counts
indicated more similarities between SKBR3 and SUM190. The top-ranking
Gene Ontology and BioCarta pathways for the cell-line specific variants
pointed to distinct key mechanisms including: amino sugar metabolism,
caspase activity, and endocytosis in SKBR3; different aspects of metabolism,
especially of lipids in SUM190; cell-to-cell adhesion, integrin, and
ERK1/ERK2 signaling; and translational control in SUM149. The analyses
indicated an enrichment in the electron transport chain processes
in the ERBB2 overexpressed cell line models and an association of
nucleotide binding, RNA splicing, and translation processes with the
IBC models, SUM190 and SUM149. Detailed experimental studies on the
distinct variants identified from each of these three breast cancer
cell line models that may open opportunities for drug target discovery
and help unveil their specific roles in cancer progression and metastasis.