Dual targeting of Src and ER prevents acquired antihormone resistance in breast cancer cells |
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Authors: | S Hiscox N J Jordan C Smith M James L Morgan K M Taylor T P Green R I Nicholson |
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Institution: | (1) Tenovus Centre for Cancer Research, Welsh School of Pharmacy, Redwood Building, King Edward VII Avenue, Cardiff, Wales, CF10 3XF, UK;(2) AstraZeneca, Alderley Park, Macclesfield, UK |
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Abstract: | Acquired resistance to endocrine therapies presents a major obstacle to the successful treatment of breast cancer patients.
Previously, we have shown that acquisition of resistance to tamoxifen in breast cancer cells is accompanied by an elevation
in Src kinase activity which promotes an aggressive, invasive phenotype in vitro. Here, we have explored the potential therapeutic
effects of combining Src inhibition with anti-oestrogen treatment on the development of endocrine insensitivity in breast
cancer cells. Treatment of MCF7 and T47D cells with tamoxifen alone resulted in an initial growth inhibitory phase followed
by the eventual development of tamoxifen resistance together with an elevation of Src kinase activity, which was central to
their increased invasive capacity. Chronic exposure of both cell types to the Src inhibitor, AZD0530, as a monotherapy resulted
in outgrowth of AZD0530-resistant cells, in which Src kinase activity remained suppressed as did their in vitro invasive nature.
Treatment of both MCF7 and T47D cells with AZD0530 in combination with tamoxifen resulted in a reduction of Src activity together
with inhibition of focal adhesion kinase phosphorylation and a complete abrogation of their in vitro invasive behaviour. Furthermore,
combination therapy significantly suppressed expression of cyclinD1 and c-myc and prevented cell proliferation and the subsequent
emergence of a resistant phenotype, with total cell loss occurring by 12 weeks. These data demonstrate that pharmacological
targeting of Src kinase, in conjunction with antihormone therapies, effectively prevents antihormone resistance in breast
cancer cells in vitro and suggests a potential novel therapeutic benefit of Src kinase inhibitors clinically. |
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Keywords: | Src ER Tamoxifen-resistance Breast cancer |
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