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MAF amplification increases the risk of breast cancer (BCa) metastasis through mechanisms that are still poorly understood yet have important clinical implications. Oestrogen-receptor-positive (ER + ) BCa requires oestrogen for both growth and metastasis, albeit by ill-known mechanisms. Here we integrate proteomics, transcriptomics, epigenomics, chromatin accessibility and functional assays from human and syngeneic mouse BCa models to show that MAF directly interacts with oestrogen receptor alpha (ERα), thereby promoting a unique chromatin landscape that favours metastatic spread. We identify metastasis-promoting genes that are de novo licensed following oestrogen exposure in a MAF-dependent manner. The histone demethylase KDM1A is key to the epigenomic remodelling that facilitates the expression of the pro-metastatic MAF/oestrogen-driven gene expression program, and loss of KDM1A activity prevents this metastasis. We have thus determined that the molecular basis underlying MAF/oestrogen-mediated metastasis requires genetic, epigenetic and hormone signals from the systemic environment, which influence the ability of BCa cells to metastasize.

Titel:	MAF amplification licenses ERα through epigenetic remodelling to drive breast cancer metastasis.
Autor/in / Beteiligte Person:	Llorente, A ; Blasco, MT ; Espuny, I ; Guiu, M ; Ballaré, C ; Blanco, E ; Caballé, A ; Bellmunt, A ; Salvador, F ; Morales, A ; Nuñez, M ; Loren, G ; Imbastari, F ; Fidalgo, M ; Figueras-Puig, C ; Gibler, P ; Graupera, M ; Monteiro, F ; Riera, A ; Holen, I ; Avgustinova, A ; Di Croce, L ; Gomis, RR
Link:	View record at Springer (Volltext)
Zeitschrift:	Nature cell biology, Jg. 25 (2023-12-01), Heft 12, S. 1833-1847
Veröffentlichung:	London : Macmillan Magazines Ltd., [1999-, 2023
Medientyp:	academicJournal
ISSN:	1476-4679 (electronic)
DOI:	10.1038/s41556-023-01281-y
Schlagwort:	Animals Female Humans Mice Cell Line, Tumor Chromatin Estrogens Histone Demethylases genetics Histone Demethylases metabolism Breast Neoplasms genetics Breast Neoplasms pathology Epigenesis, Genetic Estrogen Receptor alpha genetics Estrogen Receptor alpha metabolism Gene Amplification Proto-Oncogene Proteins c-maf genetics
Sonstiges:	Nachgewiesen in: MEDLINE Sprachen: English Publication Type: Journal Article Language: English [Nat Cell Biol] 2023 Dec; Vol. 25 (12), pp. 1833-1847. <i>Date of Electronic Publication: </i>2023 Nov 09. MeSH Terms: Breast Neoplasms* / genetics ; Breast Neoplasms* / pathology ; Epigenesis, Genetic* ; Estrogen Receptor alpha* / genetics ; Estrogen Receptor alpha* / metabolism ; Gene Amplification* ; Proto-Oncogene Proteins c-maf* / genetics ; Animals ; Female ; Humans ; Mice ; Cell Line, Tumor ; Chromatin ; Estrogens ; Histone Demethylases / genetics ; Histone Demethylases / metabolism References: Richman, J. & Dowsett, M. Beyond 5 years: enduring risk of recurrence in oestrogen receptor-positive breast cancer. Nat. Rev. Clin. Oncol. 16, 296–311 (2019). (PMID: 30563978) ; Ma, Y. et al. A new class of small molecule estrogen receptor-α antagonists that overcome anti-estrogen resistance. Oncotarget 6, 40388–40404 (2015). (PMID: 265751734747340) ; Coleman, R. E. 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(PMID: 29358704) Grant Information: GCTRA18006CARR Fundación Científica Asociación Española Contra el Cáncer (Scientific Foundation, Spanish Association Against Cancer); PRYGN223207GOMI Fundación Científica Asociación Española Contra el Cáncer (Scientific Foundation, Spanish Association Against Cancer); POSTD20038BLAS Fundación Científica Asociación Española Contra el Cáncer (Scientific Foundation, Spanish Association Against Cancer); SGR-2017-557 Generalitat de Catalunya (Government of Catalonia); PID2019-108322GB-100 Ministerio de Economía, Industria y Competitividad, Gobierno de España (Ministerio de Economía, Industria y Competitividad) Substance Nomenclature: 0 (Chromatin) ; 0 (Estrogen Receptor alpha) ; 0 (Estrogens) ; EC 1.14.11.- (Histone Demethylases) ; EC 1.5.- (KDM1A protein, human) ; 0 (MAF protein, human) ; 0 (Proto-Oncogene Proteins c-maf) Entry Date(s): Date Created: 20231109 Date Completed: 20240110 Latest Revision: 20240110 Update Code: 20240111 PubMed Central ID: PMC10709142

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MAF amplification licenses ERα through epigenetic remodelling to drive breast cancer metastasis.