Snail1-dependent p53 repression regulates expansion and activity of tumour-initiating cells in breast cancer

Abstract

The zinc-finger transcription factor Snail1 is inappropriately expressed in breast cancer and associated with poor prognosis. While interrogating human databases, we uncovered marked decreases in relapse-free survival of breast cancer patients expressing high Snail1 levels in tandem with wild-type, but not mutant, p53. Using a Snail1 conditional knockout model of mouse breast cancer that maintains wild-type p53, we find that Snail1 plays an essential role in tumour progression by controlling the expansion and activity of tumour-initiating cells in preneoplastic glands and established tumours, whereas it is not required for normal mammary development. Growth and survival of preneoplastic as well as neoplastic mammary epithelial cells is dependent on the formation of a Snail1/HDAC1/p53 tri-molecular complex that deacetylates active p53, thereby promoting its proteasomal degradation. Our findings identify Snail1 as a molecular bypass that suppresses the anti-proliferative and pro-apoptotic effects exerted by wild-type p53 in breast cancer.

Upholding a role for EMT in breast cancer metastasis

“…Furthermore, PCR analysis of the genomic DNA extracted from the remaining metastatic lesions failed to detect the Cre-recombined Snail allele, indicating that these remaining metastases probably arose due to incomplete deletion of the Snail gene in primary tumour cells 14 . These results were confirmed recently by Ni et al 20 ; together these two studies provide direct genetic evidence of a critical role of the EMT transcription factor Snail in breast cancer metastasis. Thus, we believe that the notion that the observed metastatic dissemination of mammary tumours does indeed depend on EMT programs continues to be a viable mechanism to explain metastatic dissemination.…”

EMT, CSCs, and drug resistance: the mechanistic link and clinical implications

“…For example, Snail has been reported to reduce the expression of the tumour-suppressor protein p53 in carcinoma cells via formation of a Snail–histone deacetylase 1 (HDAC1)–p53 ternary complex and subsequent deacetylation of p53, thereby promoting its protea-somal degradation 145 . Importantly, the tumour-initiating ability of neoplastic cells in the PyMT-driven mouse mammary tumour model is diminished by deletion of Snai1 , and this ability can be restored through concomitant deletion of Tp53 (encoding p53) 145 . Hence, the EMT programme seems to confer CSC phenotypes on carcinoma cells through effects on both the extracellular and intracellular signalling machinery.…”

Divergent Matrix-Remodeling Strategies Distinguish Developmental from Neoplastic Mammary Epithelial Cell Invasion Programs

“…Given this unique characteristic, the mammary gland provides a model wherein normal epithelial cells and carcinoma cells infiltrate tissues whose ECM composition and architecture are interchangeable. As such, we have compared the ECM remodeling programs mobilized during normal postnatal branching morphogenesis to those activated during breast carcinoma progression in a transgenic system that recapitulates key features of human breast carcinoma progression (Cheung et al, 2013; Ni et al, 2016; Wculek and Malanchi, 2015; Ye et al, 2015). In turn, we have identified a single proteolytic effector, the membrane-anchored metalloproteinase, Mmp14 /MT1-MMP, as the upstream regulator of normal as well as neoplastic tissue-invasive activity.…”