  Background: Differential expression analysis of (individual) genes is often
used to study their roles in diseases. However, diseases such as cancer are a
result of the combined effect of multiple genes. Gene products such as proteins
seldom act in isolation, but instead constitute stable multi-protein complexes
performing dedicated functions. Therefore, complexes aggregate the effect of
individual genes (proteins) and can be used to gain a better understanding of
cancer mechanisms. Here, we observe that complexes show considerable changes in
their expression, in turn directed by the concerted action of transcription
factors (TFs), across cancer conditions. We seek to gain novel insights into
cancer mechanisms through a systematic analysis of complexes and their
transcriptional regulation.
  Results: We integrated large-scale protein-interaction (PPI) and
gene-expression datasets to identify complexes that exhibit significant changes
in their expression across different conditions in cancer. We devised a
log-linear model to relate these changes to the differential regulation of
complexes by TFs. The application of our model on two case studies involving
pancreatic and familial breast tumour conditions revealed: (i) complexes in
core cellular processes, especially those responsible for maintaining genome
stability and cell proliferation (e.g. DNA damage repair and cell cycle) show
considerable changes in expression; (ii) these changes include decrease and
countering increase for different sets of complexes indicative of compensatory
mechanisms coming into play in tumours; and (iii) TFs work in cooperative and
counteractive ways to regulate these mechanisms. Such aberrant complexes and
their regulating TFs play vital roles in the initiation and progression of
cancer.
