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

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. mammary stem cells | p53 family | breast cancer

Gli Transcription Factors Mediate the Oncogenic Transformation of Prostate Basal Cells Induced by a Kras-Androgen Receptor Axis

“…Our results support the reciprocal regulation of Gli signaling and p63 expression for maintenance of the epidermal homeostasis of multiple organs, including normal prostate development (32). Interference with the p63 and Gli signaling interaction network leads to dysregulation of differentiation and promotes initiation of carcinogenesis (22,32,33).…”

“…Collectively, the data indicate that a fully functional AR is required for Kras signaling to pathologically regulate the transformation of basal/progenitor cells. The reciprocal interaction of p63 and Gli transcription factors is essential for the maintenance of homeostasis of epithelial cells (32,33). Thus, we further examined whether Gli signaling is essential for the expansion of p63 basal/progenitor cells in vivo.…”

Personalized Stem Cell Therapy to Correct Corneal Defects Due to a Unique Homozygous-Heterozygous Mosaicism of Ectrodactyly-Ectodermal Dysplasia-Clefting Syndrome

“…In sharp contrast, tissues generated from R279H and R304Q-p63 OMESCs showed defects in both stratification and differentiation, thus resulting in severe tissue hypoplasia and lack of proper tissue polarity (Fig. 4D), consistent with previous reports [28][29][30][31][32][33][34][35]. Collectively, these results strongly support the potential clinical use of p.R311K-p63 HHs for the development of CAOMESCs, to reconstruct the ocular surface of this unique case of EEC syndrome.…”

Vascular ageing and endothelial cell senescence: Molecular mechanisms of physiology and diseases

“…The complex balance between p53 family and HIF can impact on mitochondrial activity and redox cellular status; this might indirectly affect cellular senescence and ageing. Kim et al, 2014;Melino et al, 2015;Memmi et al, 2015;Rufini et al, 2012;Su et al, 2009;Tyner et al, 2002). All three models develop kyphosis, alopecia, premature thinning of the skin.…”