TAp63 suppresses mammary tumorigenesis through regulation of the Hippo pathway

Abstract

Mechanisms regulating the transition of mammary epithelial cells (MECs) to mammary stem cells (MaSCs) and to tumor-initiating cells (TICs) have not been entirely elucidated. The p53 family member, p63, is critical for mammary gland development and contains transactivation domain isoforms, which have tumor-suppressive activities, and the ΔN isoforms, which act as oncogenes. In the clinic, p63 is often used as a diagnostic marker, and further analysis of the function of TAp63 in the mammary gland is critical for improved diagnosis and patient care. Loss of TAp63 in mice leads to the formation of aggressive metastatic mammary adenocarcinoma at 9–16 months of age. Here we show that TAp63 is crucial for the transition of mammary cancer cells to TICs. When TAp63 is lost, MECs express embryonic and MaSC signatures and activate the Hippo pathway. These data indicate a crucial role for TAp63 in mammary TICs and provide a mechanism for its role as a tumor- and metastasis-suppressor in breast cancer.

p53 shades of Hippo

“…53 Through this capacity, LATS2 mediates p53 activation in response to a number of diverse types of stress signals, including mitotic apparatus dysfunction, expression of oncogenic RAS and cholesterol overload, 53,117,118,156 and during ESC differentiation. 52 Similarly, both YAP and TAZ collaborate with different p63 isoforms to modulate adult and CSCs, 71,86,89,90 whereas MST and YAP cooperate to direct p73-dependent apoptosis. 106,168 mutp53 physically interacts with YAP to coordinately regulate the expression of cancer-related genes.…”

“…In healthy tissue, TAp63 restricts mammary stem cell potential by inhibiting TAZ activity. 90 Mechanistically, LKB1, a transcriptional target of p63, 91 phosphorylates the microtubule affinity-regulating kinase family to safeguard LATS kinase activity. 92 In aggressive human mammary adenocarcinomas, loss of TAp63 depolarizes cells and activates TAZ (but not YAP), which endows self-renewal capacity to breast cancer cells.…”

Role of p53 family isoforms in enhancing aggressiveness and chemoresistance in pancreatic cancer (Review)

“…For instance, the study by Flores et al (2005) concluded that p63 heterogeneity leads to the development of spontaneous tumours (78), while Keyes et al (2006) came to the opposite conclusion (79). The TA and DN isoforms of p63 play various roles in normal cells, as well as in cancerous ones; TAp63 is responsible for glycolysis through liver kinase B1 (LKB1) protein kinase regulation, fatty acid oxidation, insulin secretion, pro-oxidant response, as well as female germ cell preservation (80)(81)(82)(83)(84).…”

YAP Expression and Activity Are Suppressed by S100A7 via p65/NFκB-mediated Repression of ΔNp63

“…In contrast, expression of IkB-a results in strong induction of p63 expression, indicating that p63 is, indeed, negatively regulated by NFkB (27,28). In addition, some crosstalk between p63 and the Hippo pathway has been discovered recently (25,29), for example, DNp63 directly interacts with the Hippo effector YAP and is a mediator of YAP function in the epithelium of lung airways (30). p63 coamplified with ACTL6A in SCC to drive YAP activity, which resulted in regeneration, proliferation, and poor prognosis (31).…”

“…The p63 isoforms can be placed into two groups: the transactivation domain isoforms (TAp63), which structurally resemble p53 and act as tumor suppressors; and the DN isoforms (DNp63), which bind to p53, TAp63, and TAp73 and inhibit their function, thus acting as oncogenes (22)(23)(24). Unlike DNp63, TAp63 is not expressed or is present at low levels in a variety of cancers (25,26). Recent studies reported that NFkB can suppress p63 expression through the direct interaction of p65 with the proximal region of the p63 promoter (26).…”