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MAF amplification licenses Estrogen Receptor Alpha to drive breast cancer metastasis

ABSTRACT: MAF-amplification increases the risk of breast cancer (BCa) metastasis through poorly understood mechanisms but with important clinical implications. Estrogen receptor-positive (ER+) BCa associated with estrogen (E2) dependency sustains growth of early of breast carcinomas, but ultimately, supports metastasis by unknown mechanisms. Here we integrate proteomics, (epi)genomics and functional assays derived from human and syngeneic BCa mouse models to show that MAF directly interacts with ERalpha, thereby promoting a unique chromatin state that favors the metastatic spread of ER+ BCa cells. Indeed, we identify a set of metastasis-promoting genes that are de novo licenced following EERa2-exposure in a MAF-dependent manner. Among these we found factors influence the establishment of cellular identity and with a known role in metastasis initiation (e.g. SOX9), as well as modulators of the bone stroma, which can ultimately aid in preparing the bone metastatic “soil” (e.g. FGF18, PTHLH and JAG1). Central to the epigenomic remodeling that facilitates the expression of the MAF/E2 gene set is the histone demethylase KDM1A. Indeed, loss of KDM1A activity prevents MAF/E2-mediated BCa metastasis. Collectively, here we disentangle the molecular framework that underlies MAF/E2-mediated metastasis and demonstrate that genetic, epigenetic and hormonal systemic cues are integrated in BCa cells to determine their metastatic success, and with it patient prognosis.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Epithelial Cell, Mammary Gland

DISEASE(S): Breast Adenocarcinoma

SUBMITTER: Marta Vilaseca

LAB HEAD: Roger Gomis

PROVIDER: PXD035936 | Pride | 2023-11-13

REPOSITORIES: Pride

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MAF Amplification licenses Estrogen Receptor α to Drive Breast Cancer Metastasis [RNA-seq]

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2023-09-15 | GSE210607 | GEO

Disruption of mitochondrial dynamics triggers muscle inflammation through interorganellar contacts and mtDNA mislocation

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2023-01-20 | PXD037935 | Pride

TLK2-associated intellectual disability: report of six novel cases and molecular characterization of p.(Asp551Gly) and p.(Ser617Leu) variants

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LncRNA and mRNA expression patterns in bladder cancer patients with lymph nodes metastasis.

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MAF Amplification licenses Estrogen Receptor α to Drive Breast Cancer Metastasis [dataset 2]

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MAF Amplification licenses Estrogen Receptor α to Drive Breast Cancer Metastasis [MAF ChIP-seq]

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