Multi-omics analysis identifies intrinsic Trp53 driven metastatic breast cancer subtypes [RNA-seq]

Metastatic breast cancer is the leading cause of death amongst patients that develop breast cancer. The molecular drivers of metastatic breast cancer are largely unknown. Treatment of metastatic breast cancer is limited to systemic cytotoxic chemotherapies, which often deteriorate patient quality of life, and tumors often become refractory, resulting in incurable disease. The most frequently mutated gene associated with metastatic breast cancer is TP53. The TP53R248W hotspot missense mutation is associated with poor prognosis in breast cancer. To understand the intrinsic transcriptomic and genomic landscape of metastatic breast cancer driven by mutant p53, we generated a somatic mouse model driven by mammary epithelial specific expression of Trp53R248W. Primary tumors were highly metastatic and reflected the human molecular subtypes of luminal A, luminal B, HER2, and TNBC, with TNBC comprising the majority (79%) of these tumors. Transcriptomic profiling revealed primary tumor heterogeneity characterized by three intrinsic subtypes (1) stem-cell like; (2) well-differentiated metabolic like; and (3) immune suppressed. Stem-cell like tumors activate ribosome biosynthesis and E2F signaling. These tumors harbor amplifications in Met, Birc3, Yap1 and deletions in Nf1, Pik3r1, and Rad17. Well-differentiated metabolic like mammary tumors activate cytochrome P450 enzymes, estrogen signaling and branched chain amino acid degradation and harbor mutations in the Pten pathway. Immune suppressed tumors enrich for processes related to immune suppression. These tumors have high mutation burden, frequently mutate Traf7 and delete Cdkn2a. This is the most comprehensive transcriptomic and genomic profiling of mutant p53 driven breast tumors and sheds light on their heterogenous nature and distinct intrinsic programs that may inform targeted therapy for metastatic breast cancer.