ΔNp63α Promotes Breast Cancer Cell Motility through the Selective Activation of Components of the Epithelial-to-Mesenchymal Transition Program

Abstract

Cell identity signals influence the invasive capability of tumor cells, as demonstrated by the selection for programs of epithelial-to-mesenchymal transition (EMT) during malignant progression. Breast cancer cells retain canonical epithelial traits and invade collectively as cohesive groups of cells, but the signaling pathways critical to their invasive capabilities are still incompletely understood. Here we report that the transcription factor ΔNp63α drives the migration of basal-like breast cancer (BLBC) cells by inducing a hybrid mesenchymal/epithelial state. Through a combination of expression analysis and functional testing across multiple BLBC cell populations, we determined that ΔNp63α induces migration by elevating the expression of the EMT program components Slug and Axl. Interestingly, ΔNp63α also increased the expression of miR205, which can silence ZEB1/2 to prevent the loss of epithelial character caused by EMT induction. In clinical specimens, co-expression of various elements of the ΔNp63α pathway confirmed its implication in motility signaling in BLBC. We observed that activation of the ΔNp63α pathway occurred during the transition from noninvasive ductal carcinoma in situ to invasive breast cancer. Notably, in an orthotopic tumor model, Slug expression was sufficient to induce collective invasion of E-cadherin expressing BLBC cells. Together, our results illustrate how ΔNp63α can drive breast cancer cell invasion by selectively engaging pro-migratory components of the EMT program while, in parallel, still promoting the retention of epithelial character.

ΔNp63 regulates cell proliferation, differentiation, adhesion, and migration in the BL2 subtype of basal-like breast cancer

“…p63 has also been implicated in regulating epithelial-mesenchymal transition (EMT) [38][39][40], although this is a partial effect in which ΔNp63 both promotes and inhibits different components of EMT through induction of Slug and simultaneous inhibition of ZEB1/2 [39,40]. Compatible with a partial effect of p63 on phenotypic reprogramming, we found that p63 loss causes incomplete transition from basal-type to luminal-type epithelial cells; lack of p63 in these basal cancer cells did not induce estrogen receptor and did not decrease CK5 levels.…”

A mechanism-based computational model to capture the interconnections among epithelial-mesenchymal transition, cancer stem cells and Notch-Jagged signaling

“…Previous mathematical models and experimental studies have identified multiple phenotypic stability factors (PSF) that can stabilize a hybrid E/M phenotype such as OVOL1/2 [63][64][65], GRHL2 [66], ∆NP63α [67], and NUMB/NUMBL [68] and facilitate collective cell migration. GRLH2 and OVOL1/2 directly target the miR-200-ZEB axis regulating EMT [63,66], while NUMB/NUMBL modulates EMT via Notch-Jagged signaling [68].…”

NRF2 activates a partial Epithelial-Mesenchymal Transition and is maximally present in a hybrid Epithelial/Mesenchymal phenotype

“…Mechanisms enabling cancer cells to maintain hybrid E/M phenotype(s), however, remain largely unclear. Recent experimental and computational studies have suggested that a set of 'phenotypic stability factors' (PSFs) such as GRHL2, OVOL2, ΔNp63α and NUMB can help cells in maintaining a hybrid E/M phenotype by preventing 'cells that have gained partial plasticity' from undergoing a full EMT [5][6][7][8][9][10] and thus enabling collective cell migration. Knockdown of these PSFs drove the cells to a complete EMT in vitro and in vivo, while their exogenous overexpression can drive Mesenchymal-Epithelial Transition (MET) -the reverse of EMT [11].…”