Claudin-low-like mouse mammary tumors show distinct transcriptomic patterns uncoupled from genomic drivers

• Published in: Breast cancer research : BCR 2019-07, Vol.21 (1), p.85-85, Article 85
• Main Authors: Fougner, Christian, Bergholtz, Helga, Kuiper, Raoul, Norum, Jens Henrik, Sørlie, Therese
• Format: Article
• Language: English
• Subjects: Animals; Biochemistry; Biopsy; Breast cancer; Breast tumors; Cancer; Cancer research; Care and treatment; Claudin-low; Claudins - metabolism; Disease Models, Animal; Displays (Marketing); DNA Copy Number Variations; Exome sequencing; Female; Gene expression; Gene Expression Profiling - methods; Gene Expression Regulation, Neoplastic; Genes; Genetic aspects; Genetic research; Genomics; Humans; Immunohistochemistry; Mammary Neoplasms, Animal - genetics; Mammary Neoplasms, Animal - metabolism; Mammary Neoplasms, Animal - pathology; Medroxyprogesterone; Mice; Mice, Transgenic; Motor vehicle drivers; Mouse models; Mutation; Obesity; Oncogenes; Prognosis; Stem cells; Subtypes; Transcription (Genetics); Transcriptome; Transcriptomics; Tumors
• ISSN: 1465-542X; 1465-5411; 1465-542X
• DOI: 10.1186/s13058-019-1170-8

Claudin-low breast cancer is a molecular subtype associated with poor prognosis and without targeted treatment options. The claudin-low subtype is defined by certain biological characteristics, some of which may be clinically actionable, such as high immunogenicity. In mice, the medroxyprogesterone acetate (MPA) and 7,12-dimethylbenzanthracene (DMBA)-induced mammary tumor model yields a heterogeneous set of tumors, a subset of which display claudin-low features. Neither the genomic characteristics of MPA/DMBA-induced claudin-low tumors nor those of human claudin-low breast tumors have been thoroughly explored. The transcriptomic characteristics and subtypes of MPA/DMBA-induced mouse mammary tumors were determined using gene expression microarrays. Somatic mutations and copy number aberrations in MPA/DMBA-induced tumors were identified from whole exome sequencing data. A publicly available dataset was queried to explore the genomic characteristics of human claudin-low breast cancer and to validate findings in the murine tumors. Half of MPA/DMBA-induced tumors showed a claudin-low-like subtype. All tumors carried mutations in known driver genes. While the specific genes carrying mutations varied between tumors, there was a consistent mutational signature with an overweight of T>A transversions in TG dinucleotides. Most tumors carried copy number aberrations with a potential oncogenic driver effect. Overall, several genomic events were observed recurrently; however, none accurately delineated claudin-low-like tumors. Human claudin-low breast cancers carried a distinct set of genomic characteristics, in particular a relatively low burden of mutations and copy number aberrations. The gene expression characteristics of claudin-low-like MPA/DMBA-induced tumors accurately reflected those of human claudin-low tumors, including epithelial-mesenchymal transition phenotype, high level of immune activation, and low degree of differentiation. There was an elevated expression of the immunosuppressive genes PTGS2 (encoding COX-2) and CD274 (encoding PD-L1) in human and murine claudin-low tumors. Our findings show that the claudin-low breast cancer subtype is not demarcated by specific genomic aberrations, but carries potentially targetable characteristics warranting further research.