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Breast Cancer Res. 2019 Jul 31;21(1):85. doi: 10.1186/s13058-019-1170-8.

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

Author information

1
Department of Cancer Genetics, Oslo University Hospital, Oslo, Norway.
2
Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
3
Department of Cancer Genetics, Oslo University Hospital, Oslo, Norway. therese.sorlie@rr-research.no.
4
Centre for Cancer Biomarkers CCBIO, University of Bergen, Bergen, Norway. therese.sorlie@rr-research.no.
5
Institute for Clinical Medicine, University of Oslo, Oslo, Norway. therese.sorlie@rr-research.no.

Abstract

BACKGROUND:

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.

METHODS:

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.

RESULTS:

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.

CONCLUSIONS:

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.

KEYWORDS:

Breast cancer; Claudin-low; DMBA; Genomics; MPA; Mouse models; Subtypes; Transcriptomics

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