dc.contributor.author | Fougner, Christian | |
dc.contributor.author | Bergholtz, Helga | |
dc.contributor.author | Kuiper, Raoul | |
dc.contributor.author | Norum, Jens H | |
dc.contributor.author | Sørlie, Therese | |
dc.date.accessioned | 2019-08-06T05:43:54Z | |
dc.date.available | 2019-08-06T05:43:54Z | |
dc.date.issued | 2019 | |
dc.identifier.citation | Breast Cancer Research. 2019 Jul 31;21(1):85 | |
dc.identifier.uri | http://hdl.handle.net/10852/68986 | |
dc.description.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. | |
dc.language.iso | eng | |
dc.relation.ispartof | Bergholtz, Helga (2020) Deciphering molecular heterogeneity and relevance of subtypes in breast cancer progression. Doctoral thesis http://hdl.handle.net/10852/74046 | |
dc.relation.ispartof | Fougner, Christian (2020) On the genetic determinants of cancer phenotypes. Doctoral thesis http://hdl.handle.net/10852/80847 | |
dc.relation.uri | http://hdl.handle.net/10852/74046 | |
dc.relation.uri | http://hdl.handle.net/10852/80847 | |
dc.rights | The Author(s).; licensee BioMed Central Ltd. | |
dc.rights | Attribution 4.0 International | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0/ | |
dc.title | Claudin-low-like mouse mammary tumors show distinct transcriptomic patterns uncoupled from genomic drivers | |
dc.type | Journal article | |
dc.date.updated | 2019-08-06T05:43:55Z | |
dc.creator.author | Fougner, Christian | |
dc.creator.author | Bergholtz, Helga | |
dc.creator.author | Kuiper, Raoul | |
dc.creator.author | Norum, Jens H | |
dc.creator.author | Sørlie, Therese | |
dc.identifier.doi | https://doi.org/10.1186/s13058-019-1170-8 | |
dc.identifier.urn | URN:NBN:no-72137 | |
dc.type.document | Tidsskriftartikkel | |
dc.type.peerreviewed | Peer reviewed | |
dc.identifier.fulltext | Fulltext https://www.duo.uio.no/bitstream/handle/10852/68986/1/13058_2019_Article_1170.pdf | |
dc.type.version | PublishedVersion | |
cristin.articleid | 85 | |