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

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 Bim_EL, leading to its degradation by the proteasome

CC139 fibroblasts

[132, 133]