ΔNp63 promotes stem cell activity in mammary gland development and basal-like breast cancer by enhancing Fzd7 expression and Wnt signalling

Abstract

Emerging evidence suggests that cancer is populated and maintained by tumor initiating cells (TICs) with stem-like properties similar to that of adult tissue stem cells. Despite recent advances, the molecular regulatory mechanisms that may be shared between normal and malignant stem cells remain poorly understood. Here we show that the ΔNp63 isoform of the Trp63 transcription factor promotes normal mammary stem cell (MaSC) activity by increasing the expression of the Wnt receptor Fzd7, thereby enhancing Wnt signaling. Importantly, Fzd7-dependent enhancement of Wnt signaling by ΔNp63 also governs tumor initiating activity of the basal subtype of breast cancer. These findings establish ΔNp63 as a key regulator of stem cells in both normal and malignant mammary tissues and provide direct evidence that breast cancer TICs and normal MaSCs share common regulatory mechanisms.

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

“…cbioportal.org/). As previously reported (11), our analysis of the METABRIC dataset confirmed that expression of p63 is also significantly correlated with expression of Fzd7 in patients with breast cancer, at least when using one of two distinct probes (Fig. S5 B-D).…”

“…For instance, p63 regulates the expression of several molecules of the Notch pathway (28,29). Moreover, in basal-like breast tumors, ΔNp63 regulates CSC properties through the induction of Fzd7 expression and subsequent activation of the Wnt/β-catenin pathway (11). To assess whether p63 also promotes SC activity through the modulation of these two pathways, we measured the expression levels of Notch receptors and Notch target genes, as well as the expression levels of Fzd7, in p63-depleted ErbB2 mammospheres.…”

“…Accordingly, ΔNp63 is overexpressed in the basallike subtype of breast cancer (13,14), in which a specific role for ΔNp63 in regulating CSC activity has been reported very recently (11). In differentiated mammary tumors, such as luminallike breast carcinomas, ΔNp63 expression is instead reduced during cancer progression (7).…”

“…The requirement for p63 in the morphogenesis of the mammary gland was originally suggested by the observation that complete abrogation of TP63 gene function in animal models causes loss of the mammary epithelium (8,9). Emerging evidence is pointing toward a role for p63 in regulating stemness in the adult mammary gland (3,10,11), although the clinical relevance of p63 as a SC marker in breast cancer remains poorly understood.…”

The propensity for epithelial-mesenchymal transitions is dictated by chromatin states in the cancer cell of origin

“…Along these lines, p63 normally antagonizes oncogenic TGF-β signaling and its stimulation of tumor development and metastatic progression. However, mutant p53 can form a ternary complex with TGF-β-regulated Smads and p63, thereby inactivating the tumor suppressing activities of p63 and enabling the tumor promoting properties of TGF-β, including its stimulation of metastasis and CSC self-renewal (20,21).…”