Table 1.
Cell culture based experimental characterisation of ERK1/2 association with breast cancer pregression
| Model | Reference | |
|---|---|---|
| ERK1/2 signalling | ||
| MEK1 signalling mediates transformation and metastasis | EpH4 mammary epithelial cells | [25] |
| RAF/MEK/ERK1/2 and PI3K/PTEN/AKT signalling pathways interact in breast cancer | Hematopoietic, breast (MCF7) and prostate cancer cells | [22] |
| Three-dimensional organisation | ||
| MECs fail to organise as acini because of a persistent β1-integrin-EGFR-ERK1/2 drive, but will form acini if β1-integrin, EGFR or ERK1/2 function is inhibited | HMT-3522 T-42 | [75] |
| Persistent activation of ERK1/2 impairs acinus formation and leads to invasion | HC11 MECs | [34] |
| Delayed activation of ERK1/2 impacts cell proliferation and ERα-mediated transcription | MCF7 | [82] |
| Over-expressed Par6 acts in a complex with cdc42 and aPKC to induce hyperproliferation and generate multi-acinar structures in an ERK1/2-dependent fashion | MECs | [36] |
| Activation of the ERK1/2 blocks Bim expression and correlates with protection from luminal apoptosis | MECs | [37] |
| Invasion | ||
| Ha-Ras cooperates with TGFβ to induce EMT and Raf/ERK1/2 is required | Ha-Ras-transformed MECs in 3D collagen/matrigel matrices | [40] |
| ERK1/2 signalling induces MMP expression and the duration of MAPK activation is an important determinant for certain growth factor-mediated functions | Keratinocytes | [53] |
| uPA binding to uPAR activates ERK1/2 and induces cell migration | MCF7 | [8] |
| uPA induces cell proliferation via ERK1/2 activation | MDA-MB-231 | [56] |
| uPA determines the basal level of activated ERK1/2 and prevents apoptosis | MDA-MB-231 | [57] |
| Restoration of an epithelial phenotype requires both the over-expression of E-cadherin and the suppression of ERK1/2 | MCF10A cells over-expressing activated Ras | [64] |
| Scribble co-operates with mutations in Ras and Raf to induce a migratory phenotype via induction of ERK1/2 | MCF10A | [67] |
| ECM changes impact integrin signalling and can promote mitogenic signalling through ERK1/2 | Non-malignant and human breast tumour cell line (T4-2) | [75] |
| ERK1/2 substrates, the Ets transcription factors, induce EMT and invasiveness | MECs | [76-78] |
| 'Tumour-initiating cells' can be derived from mammary cells following the activation of ERK1/2 and induction of EMT | MECs | [81] |
| ErbB/EGFR signalling to ERK1/2 | ||
| Overexpression of ErbB2 induces EMT through ERK1/2 activation | MCF10A | [90] |
| Expression of ErbB2 induces anti-apoptotic proteins Survivin and Bcl-2 via ERK1/2 and PI3K signalling | MCF7 | [87] |
| Experimentally triggered ErbB2 activation protects against apoptosis and disrupts mammary epithelial cell organisation in an ERK1/2-dependent manner | MCF10A | [88,89] |
| Progesterone receptor, IGF-1, VEGF, growth hormone and a range of ligands require EGFR to induce ERK1/2 activation | T47D, MECs | [91] |
| ER, tamoxifen resistance and ERK1/2 signalling | ||
| ERK1 and 2 are activated via oestrogen signalling through GPR30, resulting in transactivation of EGFR | MCF7, SKBR3 breast cancer cells | [10] |
| EGFR or ErbB2 resistance correlated with high ERK1/2 and AKT activity | Breast cancer cells | [9] |
| Cell survival and cell death | ||
| Survival factor-induced ERK1/2 phosphorylates BIM, inhibiting its association with BAX and proapoptotic activity | Haematopoietic cells | [134] |
| ERK1/2 phosphorylates the pro-apoptotic BCL-2 family member BimEL, leading to its degradation by the proteasome | CC139 fibroblasts | [132,133] |
aPKC = atypical PKC; EGF = epidermal growth factor; EGFR = EGF receptor; EMT = epithelial-to-mesenchymal transition; ER = oestrogen receptor; ERK = extracellular regulated kinase; IGF = insulin-like growth factor; MAPK = mitogen-activated protein kinase; MEC = mammary epithelial cell; MMP = matrix-metalloproteinase; Par = Partitioning defect; PI3K = phosphoinositide 3-kinase; PTEN, phosphatase and tensin homolog; TGF = transforming growth factor; uPA = Plasminogen activator, Urokinase; uPAR = Urokinase receptor; VEGF = vascular epidermal growth factor.