Molecular Characterisation of Feline Mammary Tumours FMCs are highly malignant tumours characterised by local invasion and early dissemination. Considering the poor outcome of affected cats identification of useful biomarkers to predict clinical behaviour and suitable therapeutic targets is of major importance. In this study we used massive parallel DNA and RNA sequencing to identify structural rearrangements and differentially expressed genes enriching key biological processes characterising FMC associated malignancy and poor outcome. Important structural rearrangements (CNLs in FCA B1 and CNGs in FCAs B4 and F2) were detected and correlated with poor prognosis. Immunohistochemical and transcriptomic findings showed a high level of correlation with genomic aberrations detected. Different potential biomarkers and therapeutic targets were identified including TUSC3 RRM2 ESRP1 HMGA2 and MYC as well as different components of the p53 and PI3K Akt signalling pathways. Amplified and upregulated genes were typically involved in pathways correlated with cell motion (SBDS ITGAM PDGFA RAC1 FGFR1 APC and ITGB2) transcription modulation (GATA3 HMGN1 ZEB1 MYC and MYCN) DNA replication and repairing (RFC3 AK2 NUDT5. MCM2 RRM2 and TYMS) and EMT elicitation (VIM ZEB1 KRAS HMGA2 ESRP1 MTDH YWHAZ and MYC). On the other hand deleted and down regulated genes were typically tumour suppressors (CSMD1 MSR1 MTUS1 TUSC3 DLC1 NRG1 and LZTS1) or genes involved in biological processes that would normally prevent tumour spreading such as tight junction components (CLDN4 CLDN5 CLDN7 CLDN8 CLDN23 LMO7 PCDH17 PCDH20 and PCDH9) and cell adhesion molecules (CD2 CD8A CD34 CD40 CDH1 CDH4 CDH5 ICAM2 ITGAM ITGB2 PECAM1 ESAM and JAM2). FMCs included in this study shared some clinical and molecular similarities with specific molecular subtypes of human breast cancer characterised by worse outcome (i.e. hTNBCs metaplastic breast carcinomas and claudin low breast tumours). Cellular models analysed shared a considerable amount of similarities with original tumours; however specific alterations mainly correlated with endocrine regulation circadian rhythm and metabolic pathways showed important differences. Despite the genomic characteristics associated with poor prognosis in solid carcinomas no separation for the different histological grouping (tubular carcinomas comedocarcinomas and solid carcinomas) was observed at the transcriptomic level. Molecular characteristics associated with malignancy were more typically observed in solid carcinomas and comedocarcinomas. However specific cases with tubular carcinomas also shared these molecular characteristics and had a poor survival. DNA and RNA high throughput sequencing prove to be useful to identify important biomarkers and target genes resemblances between FMCs and human breast cancer and advantages and limitations of in vitro models.