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 then 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.

Conclusions: Complexes in core cellular processes display considerable decreases and countering increases in

expression, strongly reflective of compensatory mechanisms in cancer. These changes are directed by the con-

certed action of cooperative and counteractive TFs. Our study highlights the roles of these complexes and TFs

and presents several case studies on compensatory processes, providing novel insights into cancer mechanisms.