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Bidirectional cross talk between ER alpha and EGFR signalling pathways regulates tamoxifen-resistant growth

Britton, David James, Hutcheson, Iain Robert, Knowlden, Janice Mary, Barrow, Denise, Giles, Martin Gwyn, McClelland, Richard Andrew, Gee, Julia Margaret Wendy ORCID: and Nicholson, Robert Ian 2006. Bidirectional cross talk between ER alpha and EGFR signalling pathways regulates tamoxifen-resistant growth. Breast Cancer Research and Treatment 96 (2) , pp. 131-146. 10.1007/s10549-005-9070-2

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We have previously demonstrated that oestrogen receptor α (ERα) modulates epidermal growth factor receptor (EGFR)/mitogen-activated protein kinase (MAPK) signalling efficiency in a tamoxifen-resistant MCF-7 breast cancer cell line (Tam-R). In the present study we have investigated whether this cross-talk between EGFR/MAPK and ERα signalling pathways is bidirectional by examining the effects of EGFR/MAPK activity on ER functionality in the same cell line. Elevated expression levels of phosphorylated serine 118 (S118) ERα were observed in the Tam-R compared to the parental wild type MCF-7 cell line (WT-MCF-7) under basal growth conditions. Phosphorylation of ERα at S118 was regulated by the EGFR/MAPK pathway in Tam-R cells being increased in response to amphiregulin (AR) and inhibited by the selective EGFR tyrosine kinase inhibitor, gefitinib and the MEK1/2 inhibitor, PD184352. Recruitment of the co-activators p68 RNA helicase and SRC1 to ERα, oestrogen response element (ERE) activity and Tam-R cell growth were similarly EGFR/MAPK-regulated. Chromatin immunoprecipitation (ChIP) studies revealed that in Tam-R cells the ERα assembled on the AR gene promoter and this was associated with elevated basal expression of AR mRNA. Furthermore, AR mRNA expression was under the regulation of the EGFR/MAPK and ERα signalling pathways. Neutralising antibodies to AR inhibited EGFR/ERK1/2 activity, reduced S118 ERα phosphorylation and reduced AR mRNA expression in TAM-R cells. These findings suggest that ERα function in Tam-R cells is maintained as a consequence of EGFR/MAPK-mediated phosphorylation at serine residue 118 resulting in the generation of a self-propogating autocrine growth-regulatory loop through the ERα-mediated production of AR.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Pharmacy
Subjects: R Medicine > RM Therapeutics. Pharmacology
Uncontrolled Keywords: amphiregulin - epidermal growth factor receptor - oestrogen receptor α - mitogen-activated protein kinase - MCF-7 cells - serine 118 - tamoxifen resistance
Publisher: Springer Verlag
ISSN: 0167-6806
Last Modified: 18 Oct 2022 14:21

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