The predominant p63 isoform, ΔNp63, is a master regulator of normal epithelial stem cell (SC) maintenance. However, in vivo evidence of the regulation of cancer stem cell (CSC) properties by p63 is still limited. Here, we exploit the transgenic MMTV-ErbB2 (v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2) mouse model of carcinogenesis to dissect the role of p63 in the regulation of mammary CSC self-renewal and breast tumorigenesis. ErbB2 tumor cells enriched for SC-like properties display increased levels of ΔNp63 expression compared with normal mammary progenitors. Down-regulation of p63 in ErbB2 mammospheres markedly restricts self-renewal and expansion of CSCs, and this action is fully independent of p53. Furthermore, transplantation of ErbB2 progenitors expressing shRNAs against p63 into the mammary fat pads of syngeneic mice delays tumor growth in vivo. p63 knockdown in ErbB2 progenitors diminishes the expression of genes encoding components of the Sonic Hedgehog (Hh) signaling pathway, a driver of mammary SC self-renewal. Remarkably, p63 regulates the expression of Sonic Hedgehog (Shh), GLI family zinc finger 2 (Gli2), and Patched1 (Ptch1) genes by directly binding to their gene regulatory regions, and eventually contributes to pathway activation. Collectively, these studies highlight the importance of p63 in maintaining the self-renewal potential of mammary CSCs via a positive modulation of the Hh signaling pathway.

Memmi, E., Sanarico, A., Giacobbe, A., Peschiaroli, A., Frezza, V., Cicalese, A., et al. (2015). p63 sustains self-renewal of mammary cancer stem cells through regulation of Sonic Hedgehog signaling. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 112(11), 3499-3504 [10.1073/pnas.1500762112].

p63 sustains self-renewal of mammary cancer stem cells through regulation of Sonic Hedgehog signaling

MELINO, GENNARO;BERNASSOLA, FRANCESCA
2015

Abstract

The predominant p63 isoform, ΔNp63, is a master regulator of normal epithelial stem cell (SC) maintenance. However, in vivo evidence of the regulation of cancer stem cell (CSC) properties by p63 is still limited. Here, we exploit the transgenic MMTV-ErbB2 (v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2) mouse model of carcinogenesis to dissect the role of p63 in the regulation of mammary CSC self-renewal and breast tumorigenesis. ErbB2 tumor cells enriched for SC-like properties display increased levels of ΔNp63 expression compared with normal mammary progenitors. Down-regulation of p63 in ErbB2 mammospheres markedly restricts self-renewal and expansion of CSCs, and this action is fully independent of p53. Furthermore, transplantation of ErbB2 progenitors expressing shRNAs against p63 into the mammary fat pads of syngeneic mice delays tumor growth in vivo. p63 knockdown in ErbB2 progenitors diminishes the expression of genes encoding components of the Sonic Hedgehog (Hh) signaling pathway, a driver of mammary SC self-renewal. Remarkably, p63 regulates the expression of Sonic Hedgehog (Shh), GLI family zinc finger 2 (Gli2), and Patched1 (Ptch1) genes by directly binding to their gene regulatory regions, and eventually contributes to pathway activation. Collectively, these studies highlight the importance of p63 in maintaining the self-renewal potential of mammary CSCs via a positive modulation of the Hh signaling pathway.
Pubblicato
Rilevanza internazionale
Articolo
Esperti anonimi
Settore BIO/11
English
breast cancer; mammary stem cells; p53 family; Animals; Cell Proliferation; Female; Gene Expression Regulation, Neoplastic; Hedgehog Proteins; Mammary Glands, Animal; Mammary Neoplasms, Experimental; Mice, Inbred C57BL; Neoplastic Stem Cells; Phosphoproteins; Receptor, ErbB-2; Trans-Activators; Transcription, Genetic; Signal Transduction
Memmi, E., Sanarico, A., Giacobbe, A., Peschiaroli, A., Frezza, V., Cicalese, A., et al. (2015). p63 sustains self-renewal of mammary cancer stem cells through regulation of Sonic Hedgehog signaling. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 112(11), 3499-3504 [10.1073/pnas.1500762112].
Memmi, E; Sanarico, A; Giacobbe, A; Peschiaroli, A; Frezza, V; Cicalese, A; Pisati, F; Tosoni, D; Zhou, H; Tonon, G; Antonov, A; Melino, G; Pelicci, P; Bernassola, F
Articolo su rivista
File in questo prodotto:
File Dimensione Formato  
Memmi et al..pdf

accesso aperto

Tipologia: Versione Editoriale (PDF)
Licenza: Copyright dell'editore
Dimensione 1.13 MB
Formato Adobe PDF
1.13 MB Adobe PDF Visualizza/Apri

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2108/132353
Citazioni
  • ???jsp.display-item.citation.pmc??? 78
  • Scopus 118
  • ???jsp.display-item.citation.isi??? 115
social impact