title: MYC-induced apoptosis in mammary epithelial cells is associated with repression of lineage-specific gene signatures.
abstract: Apoptosis caused by deregulated MYC expression is a prototype example of intrinsic tumor suppression. However, it is still unclear how supraphysiological MYC expression levels engage specific sets of target genes to promote apoptosis. Recently, we demonstrated that repression of SRF target genes by MYC/MIZ1 complexes limits AKT-dependent survival signaling and contributes to apoptosis induction. Here we report that supraphysiological levels of MYC repress gene sets that include markers of basal-like breast cancer cells, but not luminal cancer cells, in a MIZ1-dependent manner. Furthermore, repressed genes are part of a conserved gene signature characterizing the basal subpopulation of both murine and human mammary gland. These repressed genes play a role in epithelium and mammary gland development and overlap with genes mediating cell adhesion and extracellular matrix organization. Strikingly, acute activation of oncogenic MYC in basal mammary epithelial cells is sufficient to induce luminal cell identity markers. We propose that supraphysiological MYC expression impacts on mammary epithelial cell identity by repressing lineage-specific target genes. Such abrupt cell identity switch could interfere with adhesion-dependent survival signaling and thus promote apoptosis in pre-malignant epithelial tissue.
authors.affiliation: a Translational cancer biology, Research Programs Unit and Institute of Biomedicine, University of Helsinki , Helsinki , Finland.
authors.forename: Heidi M
authors.initials: HM
authors.lastname: Haikala
authors.affiliation: a Translational cancer biology, Research Programs Unit and Institute of Biomedicine, University of Helsinki , Helsinki , Finland.
authors.forename: Juha
authors.initials: J
authors.lastname: Klefström
authors.affiliation: b Theodor Boveri Institute, Biocenter, University of Würzburg, Am Hubland , Würzburg , Germany.|c Comprehensive Cancer Center Mainfranken, University of Würzburg , Würzburg , Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Eilers
authors.affiliation: b Theodor Boveri Institute, Biocenter, University of Würzburg, Am Hubland , Würzburg , Germany.|d Section of Molecular Cytology, Swammerdam Institute for Life Sciences, University of Amsterdam , Amsterdam , The Netherlands.
authors.forename: Katrin E
authors.initials: KE
authors.lastname: Wiese
mesh_terms: D000818:Animals; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D002460:Cell Line; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D005260:Female; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism; D008321:Mammary Glands, Animal / Q000166:cytology; D042361:Mammary Glands, Human / Q000166:cytology; D051379:Mice; D008856:Microscopy, Fluorescence; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000502:physiology*
chemical_list: D051741:Kruppel-Like Transcription Factors; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; C107961:ZBTB17 protein, human; D053148:Caspase 3
keywords: MIZ1; MYC; apoptosis; lineage fate; mammary epithelial cells; repression