Membrane fluidity and epidermal growth factor receptor function in breast cancer

Lindsay, Blythe (1998) Membrane fluidity and epidermal growth factor receptor function in breast cancer. PhD thesis, University of Glasgow.

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Abstract

The epidermal growth factor receptor (EGFR) has been implicated in the growth and development of a number of human cancers including breast cancer. The activity and expression of membrane associated proteins such as the EGFR may be modulated by the physical state of the membrane. Activation of the EGFR depends on the lateral diffusion and dimerisation of receptor monomers. Changes in membrane fluidity may therefore affect activation of the EGFR and hence growth signalling via this receptor. Using the technique of fluorescence recovery after photobleaching, the lateral diffusion of number of fluorescent lipid probes was studied in three breast cancer cell lines (MCF-7, MDA-MB-231 and MCF-7AdrR). The antiestrogen drug tamoxifen which is widely used in the treatment of breast cancer, was demonstrated to decrease membrane fluidity in breast cancer cells e.g. in MCF-7 cells a 24 hour incubation with l0-6M tamoxifen decreased the lateral diffusion coefficient of the AF18 probe from 203 xl0-10cm2/s to 15.4 xl0-10cm2/s. Tamoxifen treatment had a general effect on membrane fluidity which was observed using different lipid probes and was not dependent on the estrogen receptor status of the cell line. Tamoxifen's ability to decrease membrane fluidity may be due to its ability to adopt a conformation which resembles the steroid nucleus. The steroids cholesterol, 17?-estradiol and the steroidal antiestrogen ICIl82,780 all had a similar effect on membrane fluidity. Tamoxifen has previously been reported to have several actions unrelated to inhibition of estrogen action. Tamoxifen can inhibit the growth of cells in the complete absence of estrogens and also inhibit cells which do not express the estrogen receptor. Tamoxifen can inhibit EGF-stimulated growth of MCF-7 breast cancer cells by a mechanism distinct from induction of TGF? production. Tamoxifen had no effect on the cell surface expression or affinity of the EGFR and it did not inhibit the EGFR tyrosine kinase activity in isolated cell membranes. However, in intact cells tamoxifen treatment inhibited EGFR autophosphorylation. This effect could be due to stabilisation of the membrane by tamoxifen and consequent reduction in the lateral diffusion of the EGF receptor, reducing dimerisation and autophosphorylation of the receptor. This would reduce growth stimulation initiated via the EGFR. Tamoxifen can be demonstrated to reduce EGFR mobility in A431 cells. These cells have elevated levels of EGFR which allow a sufficient level of signal for FRAP measurements of receptor mobility. It is therefore possible that tamoxifen's membrane effects contribute to its anticancer action by interfering with EGFR function. The rate of internalisation of the EGFR was not altered by tamoxifen treatment which suggests that EGFR lateral diffusion is not a rate-limiting factor in receptor internalisation. Tamoxifen treatment also had no effect on the adriamycin sensitivity of the drug resistant cell line MCF-7AdrR.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Keywords: Oncology
Date of Award: 1998
Depositing User: Enlighten Team
Unique ID: glathesis:1998-71574
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 17 May 2019 09:31
Last Modified: 17 May 2019 09:31
URI: http://theses.gla.ac.uk/id/eprint/71574

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