Hypoxia, Snail and incomplete epithelial–mesenchymal transition in breast cancer

Abstract

BACKGROUND: Hypoxia is an element of the tumour microenvironment that impacts upon numerous cellular factors linked to clinical aggressiveness in cancer. One such factor, Snail, a master regulator of the epithelial -mesenchymal transition (EMT), has been implicated in key tumour biological processes such as invasion and metastasis. In this study we set out to investigate regulation of EMT in hypoxia, and the importance of Snail in cell migration and clinical outcome in breast cancer. METHODS: Four breast cancer cell lines were exposed to 0.1% oxygen and expression of EMT markers was monitored. The migratory ability was analysed following Snail overexpression and silencing. Snail expression was assessed in 500 tumour samples from premenopausal breast cancer patients, randomised to either 2 years of tamoxifen or no adjuvant treatment. RESULTS: Exposure to 0.1% oxygen resulted in elevated levels of Snail protein, along with changes in vimentin and E-cadherin expression, and in addition increased migration of MDA-MB-468 cells. Overexpression of Snail increased the motility of MCF-7, T-47D and MDA-MB-231 cells, whereas silencing of the protein resulted in decreased migratory propensity of MCF-7, MDA-MB-468 and MDA-MB-231 cells. Moreover, nuclear Snail expression was associated with tumours of higher grade and proliferation rate, but not with disease recurrence. Interestingly, Snail negativity was associated with impaired tamoxifen response (P ¼ 0.048). CONCLUSIONS: Our results demonstrate that hypoxia induces Snail expression but generally not a migratory phenotype, suggesting that hypoxic cells are only partially pushed towards EMT. Furthermore, our study supports the link between Snail and clinically relevant features and treatment response.

Classification of epithelial–mesenchymal transition phenotypes in esophageal squamous cell carcinoma is strongly associated with patient prognosis

“…3,4 Our work demonstrated that the loss of E-cadherin itself, without a mesenchymal phenotype, may not be associated with invasive behavior, whereas tumors with a mesenchymal phenotype, regardless of E-cadherin expression, showed aggressive behavior in esophageal squamous cell carcinoma. Recently, Uchikado et al 21 reported that the patients with esophageal squamous cell carcinoma who were positive for Slug expression had deeper tumor invasion and worse prognosis in the E-cadherin preserved group.…”

“…In addition, because of the dynamic and reversible nature of epithelial-mesenchymal transition, numerous advanced carcinomas that adopt some mesenchymal features retain the characteristics of well-differentiated epithelial cells. 3,4 In vivo, epithelial-mesenchymal transition phenotypes include the extremes, ranging from an epithelial phenotype to a complete mesenchymal phenotype with a variety of intermediate sub-phenotype combinations between these extremes. Examples of intermediate sub-phenotypes include the 'hybrid type' that is a mixed epithelial and mesenchymal phenotype and the 'null type' that can be defined as the loss of the epithelial phenotype without acquisition of mesenchymal phenotype.…”

MicroRNA-based regulation of epithelial–hybrid–mesenchymal fate determination

“…4B, the existence of seven possible phases (the corresponding nullclines are included in SI Appendix, Section 10): (i) monostable phenotypes-{E}, {M}, and {E/M}; (ii) coexistence of two phenotypes-{E, M}, {E, E/M}, and {E/M, M}; and (iii) coexistence of all three phenotypes-{E, E/M, M}. The richness of these identified phases can help explain experiments regarding the diverse behaviors triggered by SNAIL (34)(35)(36) in inducing EMT. According to the rate of SNAIL increase and to the details of how it is increased (e.g., by TFG-β or hypoxia, which also affect the level of ZEB), the cells will follow a different trajectory in the phase diagram and thus will go through different phenotypic transitions.…”

Krüppel-like factor 8 involved in hypoxia promotes the invasion and metastasis of gastric cancer via epithelial to mesenchymal transition

“…Under hypoxic conditions, a tumor microenvironment is generated and tumor cells undergo epithelial-to-mesenchymal transition (EMT) (9). During this process, tumor cells can adjust to the newly formed microenvironment and gain stem-cell characteristics that promote differentiation and proliferation of tumor cells.…”