title: CAF-like state in primary skin fibroblasts with constitutional BRCA1 epimutation sheds new light on tumor suppressor deficiency-related changes in healthy tissue.
abstract: Constitutive epimutations of tumor suppressor genes are increasingly considered as cancer predisposing factors equally to sequence mutations. In light of the emerging role of the microenvironment for cancer predisposition, initiation, and progression, we aimed to characterize the consequences of a BRCA1 epimutation in cells of mesenchymal origin. We performed a comprehensive molecular and cellular comparison of primary dermal fibroblasts taken from a monozygous twin pair discordant for recurrent cancers and BRCA1 epimutation, whose exceptional clinical case we previously reported in this journal. Comparative transcriptome analysis identified differential expression of extracellular matrix-related genes and pro-tumorigenic growth factors, such as collagens and CXC chemokines. Moreover, genes known to be key markers of so called cancer-associated fibroblasts (CAFs), such as ACTA2, FAP, PDPN, and TNC, were upregulated in fibroblasts of the affected twin (BRCA1(mosMe)) in comparison to those of the healthy twin (BRCA1(wt)). Further analyses detected CAF-typical cellular features, including an elevated growth rate, enhanced migration, altered actin architecture and increased production of ketone bodies in BRCA1(mosMe) fibroblasts compared to BRCA1(wt) fibroblasts. In addition, conditioned medium of BRCA1(mosMe) fibroblasts was more potent than conditioned medium of BRCA1(wt) fibroblasts to promote cell proliferation in an epithelial and a cancer cell line. Our data demonstrate, that a CAF-like state is not an exclusive feature of tumor-associated tissue but also exists in healthy tissue with tumor suppressor deficiency. The naturally occurring phenomenon of twin fibroblasts differing in their BRCA1 methylation status revealed to be a unique powerful tool for exploring tumor suppressor deficiency-related changes in healthy tissue, reinforcing their significance for cancer predisposition.
authors.affiliation: a Institute of Human Genetics, University Medical Center of the Johannes Gutenberg University Mainz , Mainz , Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Etzold
authors.affiliation: a Institute of Human Genetics, University Medical Center of the Johannes Gutenberg University Mainz , Mainz , Germany.
authors.forename: Danuta
authors.initials: D
authors.lastname: Galetzka
authors.affiliation: a Institute of Human Genetics, University Medical Center of the Johannes Gutenberg University Mainz , Mainz , Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Weis
authors.affiliation: a Institute of Human Genetics, University Medical Center of the Johannes Gutenberg University Mainz , Mainz , Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Bartsch
authors.affiliation: b Institute of Human Genetics, Julius Maximilians University , Würzburg , Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Haaf
authors.affiliation: c Institute of Medical Biometry, Epidemiology and Informatics, University Medical Center of the Johannes Gutenberg University Mainz , Mainz , Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Spix
authors.affiliation: c Institute of Medical Biometry, Epidemiology and Informatics, University Medical Center of the Johannes Gutenberg University Mainz , Mainz , Germany.
authors.forename: Timo
authors.initials: T
authors.lastname: Itzel
authors.affiliation: a Institute of Human Genetics, University Medical Center of the Johannes Gutenberg University Mainz , Mainz , Germany.
authors.forename: Susann
authors.initials: S
authors.lastname: Schweiger
authors.affiliation: d First Department of Internal Medicine , University Medical Center of the Johannes Gutenberg University Mainz , Mainz , Germany.
authors.forename: Dennis
authors.initials: D
authors.lastname: Strand
authors.affiliation: d First Department of Internal Medicine , University Medical Center of the Johannes Gutenberg University Mainz , Mainz , Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Strand
authors.affiliation: a Institute of Human Genetics, University Medical Center of the Johannes Gutenberg University Mainz , Mainz , Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Zechner
mesh_terms: D000328:Adult; D019313:BRCA1 Protein / Q000235:genetics*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D017077:Culture Media, Conditioned; D016207:Cytokines / Q000235:genetics; D019175:DNA Methylation; D016326:Extracellular Matrix Proteins / Q000235:genetics; D005260:Female; D005347:Fibroblasts / Q000166:cytology* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D005801:Genes, Homeobox; D016147:Genes, Tumor Suppressor; D057895:Haploinsufficiency; D006801:Humans; D007657:Ketone Bodies / Q000378:metabolism; D009154:Mutation; D009364:Neoplasm Recurrence, Local / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D012867:Skin / Q000166:cytology; D059467:Transcriptome; D014427:Twins
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D017077:Culture Media, Conditioned; D016207:Cytokines; D016326:Extracellular Matrix Proteins; D007657:Ketone Bodies
keywords: BRCA1; cancer predisposition; cancer-associated fibroblasts, CAFs; epimutation; mosaic; primary fibroblasts; promoter methylation; tumor-suppressor deficiency