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Tamoxifen-resistance in MCF7 cells promotes EMT-like behaviour and involves modulation of [beta]-catenin phosphorylation

Hiscox, Stephen Edward ORCID:, Jiang, Wen Guo ORCID:, Obermeier, Kathrin, Taylor, Kathryn Mary ORCID:, Morgan, Liam David ORCID:, Burmi, Rajpal Singh, Barrow, Denise and Nicholson, Robert Ian 2006. Tamoxifen-resistance in MCF7 cells promotes EMT-like behaviour and involves modulation of [beta]-catenin phosphorylation. International journal of cancer 118 (2) , pp. 290-301. 10.1002/ijc.21355

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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 epithelialto-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 b-catenin, whilst serine/threoninephosphorylated b-catenin was decreased. These cells also displayed loss of association between b-catenin and E-cadherin, increased cytoplasmic and nuclear b-catenin and elevated transcription of b-catenin target genes known to be involved in tumour progression and EMT. Inhibition of EGFR kinase activity in TamR cells reduced b-catenin tyrosine phosphorylation, increased b-catenin–E-cadherin association and promoted cell–cell adhesion. In such treated cells, the association of b-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 b-catenin and may contribute to an enhanced aggressive phenotype and transition towards a mesenchymal phenotype in vitro.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Pharmacy
ISSN: 10970215
Last Modified: 03 Feb 2023 02:06

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