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 adhesiondependent survival signaling and thus promote apoptosis in pre-malignant epithelial tissue.

Peri‐weaning cholera toxin consumption suppresses chemically‐induced carcinogenesis in mice

“…Unraveling the complicate immune system‐related apoptotic signaling in different epithelia falls beyond the scope of our study. Yet, our findings in the mammary tissue associating CT with decreased cytoplasmic and increased nuclear p21, and the downregulation of c‐Myc and Runx2 are in line with this notion 37–40 . In agreement with this are also the downregulation of Klf4 in the lung and of Runx3 in the squamous stomach epithelium 41 .…”

“…Yet, our findings in the mammary tissue associating CT with decreased cytoplasmic and increased nuclear p21, and the downregulation of c-Myc and Runx2 are in line with this notion. [37][38][39][40] In agreement with this are also the downregulation of Klf4 in the lung and of Runx3 in the squamous stomach epithelium. 41 On the other hand, other effects of CT on mammary and nonglandular stomach tissues, including downregulation of Her2/neu oncogene, 34,36 and Snai2 and Id2 transcription factors, 16 did not co-exist with a decreased epithelial cell proliferation, as determined by CyclinD1 and Ki-67 immunostainings.…”

Proteomic Analysis of Breast Cancer Resistance to the Anticancer Drug RH1 Reveals the Importance of Cancer Stem Cells

“…Eight phosphosites belonging to seven proteins that could be phosphorylated by JNK kinase were identified. This includes mTOR interaction partner RPTOR, and the prominent JNK targets JUN and STAT1, all of which are involved in the induction of apoptosis [50,51,52], cell cycle arrest [53,54,55] and transcription control [56,57,58]. Other JNK targets are less phosphorylated in the drug-resistant cells, including LMO7 involved in ubiquitination [59], DCP1A in mRNA decapping [60] and STMN1 that contributes to microtubule depolymerization [61].…”

Increased expression of Myc‑interacting zinc finger protein 1 in APP/PS1 mice

“…Miz1 serves a critical role in regulating proliferation, differentiation, cell cycle progression, and apoptosis ( 35 – 37 ). It also mediates DNA damage responses, lymphoid development and inflammation via transcriptional activation and repression of target genes ( 29 ).…”