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Identifying Modifiers of Tamoxifen Sensitivity Using High-Throughput Genetic and Chemical Screens

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Therapeutic Resistance to Anti-Hormonal Drugs in Breast Cancer

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Abstract

Endocrine therapies, which inhibit estrogen receptor (ERα) signalling, are the most common and effective treatments for ERα positive breast cancer. However, the utility of these agents is limited by the frequent development of resistance. The precise mechanisms underlying endocrine therapy resistance remain incompletely understood. In our laboratory, an RNA interference (RNAi) screen was used to identify modifiers of sensitivity to the most commonly used endocrine therapy, tamoxifen. The cyclin-dependent kinase 10 (CDK10) gene was identified as an important determinant of resistance and the mechanism whereby this gene modulates sensitivity to tamoxifen was investigated further. Silencing of CDK10 gene expression was shown to activate the MAPK signalling pathway, circumventing the reliance of breast cancer cells upon estrogen signalling. Patients with ERα positive breast tumours that express low levels of CDK10 were shown to relapse early on tamoxifen and methylation of the CDK10 gene promoter was observed in a significant proportion of patients, suggesting a mechanism for loss of CDK10 expression in tamoxifen resistant tumours. By suppressing gene expression RNAi, to a certain extent, models the pharmacological inhibition of a target protein. We performed parallel small molecule screens alongside the RNAi screen to identify compounds that sensitise to tamoxifen. Both the RNAi and small molecule screens identified the PDK1 pathway as a potential target for sensitisation to inhibit the development of endocrine therapy resistance.

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  1. The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, SW3 6JB, UK

    Alan Ashworth

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  1. Elizabeth Iorns
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  2. Christopher J. Lord
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  3. Alan Ashworth
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  1. Tenovus Centre for Cancer Research Cardiff University, Cardiff University Welsh School of Pharmacy, Cardiff, Wales, UK

    Stephen Hiscox , Julia Gee  & Robert I. Nicholson ,  & 

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Iorns, E., Lord, C.J., Ashworth, A. (2009). Identifying Modifiers of Tamoxifen Sensitivity Using High-Throughput Genetic and Chemical Screens. In: Hiscox, S., Gee, J., Nicholson, R.I. (eds) Therapeutic Resistance to Anti-Hormonal Drugs in Breast Cancer. Springer, Dordrecht. https://doi.org/10.1007/978-1-4020-8526-0_9

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