Tamoxifen resistance in MCF7 cells promotes EMT-like behaviour and involves modulation of beta-catenin phosphorylation.
We have previously demonstrated that, following acquisition of endocrine resistance, breast cancer cells display an altered growth rate together with increased aggressive behaviour in vitro. Since dysfunctional cell-cell adhesive interactions can promote an aggressive phenotype, we investigated the integrity of this protein complex in our breast cancer model of tamoxifen resistance. In culture, tamoxifen-resistant MCF7 (TamR) cells grew as loosely packed colonies with loss of cell-cell junctions and demonstrated altered morphology characteristic of cells undergoing epithelial-to-mesenchymal transition (EMT). Neutralising E-cadherin function promoted the invasion and inhibited the aggregation of endocrine-sensitive MCF7 cells, whilst having little effect on the behaviour of TamR cells. Additionally, TamR cells had increased levels of tyrosine-phosphorylated beta-catenin, whilst serine/threonine-phosphorylated beta-catenin was decreased. These cells also displayed loss of association between beta-catenin and E-cadherin, increased cytoplasmic and nuclear beta-catenin and elevated transcription of beta-catenin target genes known to be involved in tumour progression and EMT. Inhibition of EGFR kinase activity in TamR cells reduced beta-catenin tyrosine phosphorylation, increased beta-catenin-E-cadherin association and promoted cell-cell adhesion. In such treated cells, the association of beta-catenin with Lef-1 and the transcription of c-myc, cyclin-D1, CD44 and COX-2 were also reduced. These results suggest that homotypic adhesion in tamoxifen-resistant breast cancer cells is dysfunctional due to EGFR-driven modulation of the phosphorylation status of beta-catenin and may contribute to an enhanced aggressive phenotype and transition towards a mesenchymal phenotype in vitro.
Hiscox
Stephen
S
Tenovus Centre for Cancer Research, Welsh School of Pharmacy, Cardiff University, Cardiff, United Kingdom. HiscoxSE1@cf.ac.uk
Jiang
Wen Go
WG
Obermeier
Kathrin
K
Taylor
Kathryn
K
Morgan
Liam
L
Burmi
Raj
R
Barrow
Denise
D
Nicholson
Robert I
RI
D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000473:pathology*; D002448:Cell Adhesion; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000502:physiology; D005260:Female; D006801:Humans; D010641:Phenotype; D010766:Phosphorylation; D013629:Tamoxifen / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D051176:beta Catenin / Q000378:metabolism*
D018931:Antineoplastic Agents, Hormonal; D051176:beta Catenin; D013629:Tamoxifen; D066246:ErbB Receptors