Increased constitutive activity of PKB/Akt in tamoxifen resistant breast cancer MCF-7 cells

Jordan, Nicola Jane, Gee, Julia Margaret Wendy ORCID: https://orcid.org/0000-0001-6483-2015, Barrow, Denise, Wakeling, A. E. and Nicholson, Robert Ian 2004. Increased constitutive activity of PKB/Akt in tamoxifen resistant breast cancer MCF-7 cells. Breast Cancer Research and Treatment 87 (2) , pp. 167-180. 10.1023/B:BREA.0000041623.21338.47

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Abstract

The tamoxifen-resistant (TAM-R) MCF-7 breast cancer cell line has been used as a model to identify the signalling pathways that enable resistant cancer cells to grow independently of steroid hormones. In TAM-R cells, peptide growth factor signalling pathways appear to be important in modified cell behaviour, growth and survival. The PI3 kinase signalling components Akt1 and Akt2 are expressed at similar levels by both parental wild-type MCF-7 and TAM-R cells, but Akt1 phosphorylation is significantly increased in TAM-R cells grown under basal conditions. High levels of basal Akt, GSK3/ and p70S6 kinase phosphorylation are all inhibited by the PI3 kinase inhibitor, LY 294002. The ligands for the EGFR/erbB1 receptor, EGF (epidermal growth factor) and TGF(transforming growth factor-) demonstrate an increased ability to activate Akt in TAM-R compared with parental MCF-7 cells and it is proposed that the preferred autocrine or paracrine activation of Akt occurs via the erbB heterodimer EGFR/erbB2 in TAM-R cells. Akt phosphorylation is reduced by gefitinib (Iressa/ZD1839). The results suggest that the PI3 kinase pathway plays a role in proliferation of TAM-R cells and is important in the increased EGF induced membrane ruffling detected in the resistant cells. Increased Akt1 activation may contribute to the aggressive phenotype of tamoxifen resistant ER (oestrogen receptor) positive breast cancers.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Pharmacy
Subjects:	R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer) R Medicine > RM Therapeutics. Pharmacology
Uncontrolled Keywords:	Akt/PKB - breast cancer - epidermal growth factor (EGF) - EGFR/erbB2 - gefitinib/Iressa/ZD1839 - MCF-7 - PI3-kinase - Tamoxifen-resistance
Publisher:	Springer Verlag
ISSN:	0167-6806
Last Modified:	18 Oct 2022 14:21
URI:	https://orca.cardiff.ac.uk/id/eprint/17191

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