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A Pygopus 2-Histone...
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Saxena, MeeraUniv Basel, Switzerland
(författare)
A Pygopus 2-Histone Interaction Is Critical for Cancer Cell Dedifferentiation and Progression in Malignant Breast Cancer
- Artikel/kapitelEngelska2020
Förlag, utgivningsår, omfång ...
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AMER ASSOC CANCER RESEARCH,2020
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printrdacarrier
Nummerbeteckningar
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LIBRIS-ID:oai:DiVA.org:liu-170163
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https://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-170163URI
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https://doi.org/10.1158/0008-5472.CAN-19-2910DOI
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Språk:engelska
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Sammanfattning på:engelska
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Klassifikation
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Ämneskategori:ref swepub-contenttype
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Ämneskategori:art swepub-publicationtype
Anmärkningar
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Funding Agencies|SystemsX.ch MTD project MetastasiX [2014/268]; Swiss National Science FoundationSwiss National Science Foundation (SNSF) [310030B_163471, CRSII3_136274]; Swiss Cancer League [KFS-3479-08-2014]; Krebsliga Beider Basel [KlbB-4469-03-2018]
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Pygopus 2 (Pygo2) is a coactivator of Wnt/b-catenin signaling that can bind bi- or trimethylated lysine 4 of histone-3 (H3K4me(2/3)) and participate in chromatin reading and writing. It remains unknown whether the Pygo2-H3K4me(2/3) association has a functional relevance in breast cancer progression in vivo. To investigate the functional relevance of histone-binding activity of Pygo2 in malignant progression of breast cancer, we generated a knock-in mouse model where binding of Pygo2 to H3K4me(2/3) was rendered ineffective. Loss of Pygo2-histone interaction resulted in smaller, differentiated, and less metastatic tumors, due, in part, to decreased canonical Wnt/b-catenin signaling. RNA- and ATAC-sequencing analyses of tumor-derived cell lines revealed downregulation of TGF beta signaling and upregulation of differentiation pathways such as PDGFR signaling. Increased differentiation correlated with a luminal cell fate that could be reversed by inhibition of PDGFR activity. Mechanistically, the Pygo2-histone interaction potentiated Wnt/beta-catenin signaling, in part, by repressing the expression of Wnt signaling antagonists. Furthermore, Pygo2 and beta-catenin regulated the expression of miR-29 family members, which, in turn, repressed PDGFR expression to promote dedifferentiation of wild-type Pygo2 mammary epithelial tumor cells. Collectively, these results demonstrate that the histone binding function of Pygo2 is important for driving dedifferentiation and malignancy of breast tumors, and loss of this binding activates various differentiation pathways that attenuate primary tumor growth and metastasis formation. Interfering with the Pygo2-H3K4me(2/3) interaction may therefore serve as an attractive therapeutic target for metastatic breast cancer. Significance: Pygo2 represents a potential therapeutic target in metastatic breast cancer, as its histone-binding capability promotes beta-catenin-mediated Wnt signaling and transcriptional control in breast cancer cell dedifferentiation, EMT, and metastasis.
Ämnesord och genrebeteckningar
Biuppslag (personer, institutioner, konferenser, titlar ...)
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Kalathur, Ravi K. R.Univ Basel, Switzerland; Royal Childrens Hosp, Australia
(författare)
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Rubinstein, NataliaUniv Basel, Switzerland; Univ Buenos Aires, Argentina
(författare)
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Vettiger, AndreaUniv Basel, Switzerland; Harvard Med Sch, MA 02115 USA
(författare)
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Sugiyama, NamiUniv Basel, Switzerland
(författare)
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Neutzner, MelanieUniv Basel, Switzerland
(författare)
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Coto-Llerena, MaireneUniv Hosp Basel, Switzerland
(författare)
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Kancherla, VenkateshUniv Hosp Basel, Switzerland
(författare)
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Ercan, CanerUniv Hosp Basel, Switzerland
(författare)
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Piscuoglio, SalvatoreUniv Hosp Basel, Switzerland
(författare)
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Fischer, JonasUniv Basel, Switzerland
(författare)
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Fagiani, ErnestaUniv Basel, Switzerland
(författare)
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Cantù, ClaudioLinköpings universitet,Avdelningen för molekylär medicin och virologi,Medicinska fakulteten,Univ Zurich, Switzerland(Swepub:liu)claca29
(författare)
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Basler, KonradUniv Zurich, Switzerland
(författare)
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Christofori, GerhardUniv Basel, Switzerland
(författare)
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Univ Basel, SwitzerlandUniv Basel, Switzerland; Royal Childrens Hosp, Australia
(creator_code:org_t)
Sammanhörande titlar
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Ingår i:Cancer Research: AMER ASSOC CANCER RESEARCH80:17, s. 3631-36480008-54721538-7445
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Saxena, Meera
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Kalathur, Ravi K ...
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Rubinstein, Nata ...
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Vettiger, Andrea
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Sugiyama, Nami
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Neutzner, Melani ...
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visa fler...
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Coto-Llerena, Ma ...
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Kancherla, Venka ...
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Ercan, Caner
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Piscuoglio, Salv ...
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Fischer, Jonas
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Fagiani, Ernesta
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Cantù, Claudio
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Basler, Konrad
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Christofori, Ger ...
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och Cell och molekyl ...
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Cancer Research
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