Upregulation of RNA Polymerase (Pol I)-mediated transcription of rRNA (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.

Mammary epithelial morphogenesis and early breast cancer : Evidence of involvement of basal components of the RNA Polymerase I transcription machinery / S. Rossetti, A.J. Wierzbicki, N. Sacchi. - In: CELL CYCLE. - ISSN 1538-4101. - 15:18(2016), pp. 2515-2526.

Mammary epithelial morphogenesis and early breast cancer : Evidence of involvement of basal components of the RNA Polymerase I transcription machinery

N. Sacchi
Ultimo
2016

Abstract

Upregulation of RNA Polymerase (Pol I)-mediated transcription of rRNA (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.
ADH; breast cancer; DCIS; mammary epithelial morphogenesis; ribosomal gene transcription; rna polymerase i; rrn3/tif-ia; rrna; small molecule drugs; medicine (all); molecular biology; developmental biology; cell biology
Settore BIO/11 - Biologia Molecolare
2016
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/433650
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