Table 2.
EMT signalling pathways and EMT-TFs: contributions to drug resistance. Several recent studies describe EMT pathways and transcription factors which have been demonstrated to be involved in drug resistance in cancer
| Mechanism of resistance | Tissue type | Study | ||
|---|---|---|---|---|
| Signalling pathway | ||||
| TGF-β | Upregulation of TGFβ | Colon cancer cells | [59] | |
| - | Triple negative breast cancer | [63] | ||
| - | Squamous cell carcinoma stem cells | [64] | ||
| - | Breast cancer cells (HMLER) | [65] | ||
| Regulating the expression of PDK4 | Colorectal cancer | [66] | ||
| Wnt | Trastuzumab resistance associated with Wnt3 overexpression activates Wnt/β-catenin which transactivates EGFR | HER2-over expressing breast cancer | [60] | |
| Resistance to platinum-based chemotherapies. DACT1 demonstrated to be a negative regulator in EOC, inhibiting Wnt signalling and cis-platinum resistance through regulation of autophagy | Type I epithelial ovarian cancer (EOC) | [67] | ||
| NANOGP8 is main regulator. It is closely related to EMT and the Wnt pathway, and correlates with migration, invasion and chemo resistance in gastric cancer | Gastric cancer cells | [68] | ||
| Hh | Hh pathway activated in EGFR-WT and EGFR-MT lung cancer | NSCLC | [61] | |
| Hh pathway activation, EGFR and EPHB3 crosstalk through Hh-STAT3. However, loss of Hh may result in cells being more EGFR-dependent | Colorectal cancer | [69] | ||
| Notch | Activation of notch signalling | Pancreatic cancer | [62] | |
| EMT-TF | ||||
| TWIST | - | Colorectal carcinoma | [70] | |
| TWIST upregulation | Nasopharyngeal carcinoma | [71] | ||
| Activated Twist mediates P-glycoprotein expression | Bladder cancer | [72] | ||
| - | Breast cells | [73] | ||
| Snail1/2 | - | Ovarian adenocarcinoma | [74] | |
| - | HGSOC | [75] | ||
| - | Oral squamous cell carcinoma | [76] | ||
| ABC transporters are overexpressed in cancer and can remove cytotoxic drugs by ATP-dependent efflux. EMT-TF such as TWIST, SNAIL and FOXC2 have been demonstrated to increased levels of ABC transporters, which are directly related to drug resistance | Breast | [77,78] | ||
| ZEB1 | ZEB1-miR200 feedback loop. ROBO1, OLIG2, CD133 and MGMT identified as novel ZEB1 targets | Glioblastoma | [79] | |
| Increased IL-1β increases ZEB1 and was associated with increased resistance | Colon cancer | [80] | ||
| ZEB2 | Loss of FBXW7 | Colorectal cancer | [81] | |
PDK4: pyruvate dehydrogenase kinase 4; DACT1: dapper1 antagonist of catenin 1; EOC: epithelial ovarian cancer; EMT: epithelial-mesenchymal transition; EMT-TF: EMT specific transcription factor; NSCLC: non-small cell lung cancer; Hh: hedgehog; HGSOC: high grade serous ovarian cancer; Wnt: Wingless/Int1; EGFR: epidermal growth factor receptor; WT: wild type; MT: mutant; ABC: ATP-binding cassette; EPHB3: EPH Receptor B3; STAT3: signal transducer and activator of transcription 3; FOXC2: forkhead box C2; ZEB: zinc finger E-box binding homeobox; ROBO1: roundabout guidance receptor 1; OLIG2: oligodendrocyte transcription factor 2; MGMT: O-6-methylguanine-DNA methyltransferase; IL-1β: interleukin 1 beta; FBXW7: F-box and WD repeat domain containing 7