title: Mammary epithelial morphogenesis and early breast cancer. Evidence of involvement of basal components of the RNA Polymerase I transcription machinery.
abstract: Upregulation of RNA Polymerase (Pol I)-mediated transcription of rRNA and increased ribogenesis are hallmarks of breast cancer. According to several datasets, including The Cancer Genome Atlas (TCGA), amplification/upregulation of genes encoding for basal components of the Pol I transcriptional machinery is frequent at different breast cancer stages. Here we show that knock down of the RNA polymerase I-specific transcription initiation factor RRN3 (TIF-IA) in breast cancer cells is sufficient to reduce rRNA synthesis and inhibit cell proliferation, and second that stable ectopic expression of RRN3 in human mammary epithelial (HME1) cells, by increasing rRNA transcription, confers increased sensitivity to the anti-proliferative effects of a selective Pol I inhibitor. Further, RRN3-overexpressing HME1 cells, when grown in in vitro 3-dimensional (3D) culture, develop into morphologically aberrant acinar structures lacking a lumen and filled with proliferative cells, thus acquiring a morphology resembling in situ ductal breast cancer lesions (DCIS). Consequently, interference with RRN3 control of Pol I transcription seems capable of both compromising mammary epithelial morphogenetic processes at early breast cancer stages, and driving breast cancer progression by fostering proliferation.
authors.affiliation: a Department of Cancer Genetics , Roswell Park Cancer Institute , Buffalo , NY , USA.
authors.forename: Stefano
authors.initials: S
authors.lastname: Rossetti
authors.affiliation: a Department of Cancer Genetics , Roswell Park Cancer Institute , Buffalo , NY , USA.
authors.forename: Andrzej J
authors.initials: AJ
authors.lastname: Wierzbicki
authors.affiliation: a Department of Cancer Genetics , Roswell Park Cancer Institute , Buffalo , NY , USA.
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Sacchi
mesh_terms: D052160:Benzothiazoles / Q000494:pharmacology; D001943:Breast Neoplasms / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D005260:Female; D055785:Gene Knockdown Techniques; D015894:Genome, Human; D006801:Humans; D061986:MCF-7 Cells; D042361:Mammary Glands, Human / Q000473:pathology*; D009024:Morphogenesis / Q000187:drug effects / Q000235:genetics*; D009287:Naphthyridines / Q000494:pharmacology; D009361:Neoplasm Invasiveness; D035463:Pol1 Transcription Initiation Complex Proteins / Q000235:genetics / Q000378:metabolism; D055550:Protein Stability / Q000187:drug effects; D012318:RNA Polymerase I / Q000235:genetics*; D012335:RNA, Ribosomal / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects; D015854:Up-Regulation / Q000235:genetics
chemical_list: D052160:Benzothiazoles; C557717:CX 5461; D009287:Naphthyridines; D035463:Pol1 Transcription Initiation Complex Proteins; D012335:RNA, Ribosomal; C428423:RRN3 protein, human; D012318:RNA Polymerase I
keywords: ADH; DCIS; RNA polymerase I; RRN3/TIF-IA; Ribosomal gene transcription; breast cancer; mammary epithelial morphogenesis; rRNA; small molecule drugs