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Table 1 Cell culture based experimental characterisation of ERK1/2 association with breast cancer pregression

From: Key signalling nodes in mammary gland development and cancer. Mitogen-activated protein kinase signalling in experimental models of breast cancer progression and in mammary gland development

  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 [7678]
'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]
  1. 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.