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Understanding the mechanisms underlying tumour heterogeneity is key to development of treatments that can target specific tumour subtypes. We have previously targeted CRE recombinase-dependent conditional deletion of the tumour suppressor genes Brca1, Brca2, p53 and/or Pten to basal or luminal ER− cells of the mouse mammary epithelium. We demonstrated that both the cell-of-origin and the tumour-initiating genetic lesions co-operate to influence mammary tumour phenotype. Here, we use a CRE-activated HER2 orthologue to specifically target HER2/ERBB2 oncogenic activity to basal or luminal ER− mammary epithelial cells and carry out a detailed analysis of the tumours which develop. We find that in contrast to our previous studies, basal epithelial cells are refractory to transformation by the activated NeuKI allele, with mammary epithelial tumour formation largely confined to luminal ER− cells. Histologically, the majority of tumours that developed were classified as either adenocarcinomas of no special type or metaplastic adenosquamous tumours. Remarkably, the former were more strongly associated with virgin animals and were typically characterised by amplification of the NeuNT/ErbB2 locus and activation of non-canonical WNT signalling. In contrast, tumours characterised by squamous metaplasia were associated with animals that had been through at least one pregnancy and typically had lower levels of NeuNT/ErbB2 locus amplification but had activated canonical WNT signalling. Squamous changes in these tumours were associated with activation of the Epidermal Differentiation Cluster. Thus, in this model of HER2 breast cancer, cell-of-origin, reproductive history, NeuNT/ErbB2 locus amplification, and the activation of specific branches of the WNT signalling pathway all interact to drive inter-tumour heterogeneity.

Long non-coding RNAs (lncRNAs) are emerging as crucial regulators of cellular processes in diseases such as cancer, although the functions of most remain poorly understood. To address this, here we apply a novel strategy to integrate gene expression profiles across 32 cancer types, and cluster human lncRNAs based on their pan-cancer protein-coding gene associations. By doing so, we derive 16 lncRNA modules whose unique properties allow simultaneous inference of function, disease specificity and regulation for over 800 lncRNAs. Remarkably, modules could be grouped into just four functional themes: transcription regulation, immunological, extracellular, and neurological, with module generation frequently driven by lncRNA tissue specificity. Notably, three modules associated with the extracellular matrix represented potential networks of lncRNAs regulating key events in tumour progression. These included a tumour-specific signature of 33 lncRNAs that may play a role in inducing epithelialmesenchymal transition through modulation of TGFβ signalling, and two stromal-specific modules comprising 26 lncRNAs linked to a tumour suppressive microenvironment, and 12 lncRNAs related to cancer-associated fibroblasts. At least one member of the 12-lncRNA signature was experimentally supported by siRNA knockdown, which resulted in attenuated differentiation of quiescent fibroblasts to a cancer-associated phenotype. Overall, the study provides a unique pan-cancer perspective on the lncRNA functional landscape, acting as a global source of novel hypotheses on lncRNA contribution to tumour progression.Author SummaryThe established view of protein production is that genomic DNA is transcribed into RNA, which is then translated into protein. Proteins play a critical role in shaping the function of each individual cell in the human body yet they represent less than 2% of human genomic sequence whilst up to 90% of the genome is transcribed. To explain this disparity, the existence of thousands of long non-coding RNAs (lncRNAs) has emerged that do not encode proteins but perform function as an RNA molecule. Most lncRNAs have yet to be assigned a specific biological role, so to address this we apply a novel computational approach to characterise the function of >800 lncRNAs through consistent association with protein coding genes across multiple cancer types. By doing so, we discover 16 “modules” of closely related lncRNAs that share broad functional themes, the most compelling of which consists of 12 lncRNAs that could regulate activation of specific cells neighbouring the tumour, leading to accelerated tumour progression and invasion. Overall, the study provides the most robust view of the lncRNA-protein coding gene landscape to date, adding to growing evidence that lncRNAs are key regulators of cancer, and have therapeutic potential comparable to proteins.