Transcriptional Coregulators as Targets in Breast Cancer Treatment

Gene expression by ERa requires multiple chromatin changes, changes that are mediated by transcriptional coregulator complexes. The last few years have shown that several coactivators and corepressors are likely to be important for endocrine response and resistance in breast cancer, in particular, the coactivators SRC1, AIB1 and the corepressors NCoR, SMRT. The importance of these proteins in crosstalk with growth factor signalling indicates that they may be important downstream targets of growth factor receptor and protein kinase inhibitors currently being evaluated in the clinic. In addition, SRC1 and AIB1 are subject to other modifications, in particular acetylation, ubiquitination and SUMOylation (Lonard and O'Malley 2007; Lonard and O'Malley 2008), with the modifications determining their activity and turnover, a better understanding of which may provide additional methods for drug development. As SRC1 and AIB1 appear to act by facilitating the recruitment of histone acetyltransferases, namely CBP/p300 and P/CAF, and the histone methyl-transferases CARM1 and PRMT1, small molecule inhibitors of these enzymes may provide additional agents for the treatment of endocrine resistant breast cancer. An interesting additional possibility is provided by the recent observation that expression of estrogen-regulated genes requires topoisomerase II6 and PARP-1-mediated double-strand DNA break (Ju et al. 2006), raising the possibility of using PARP inhibitors for blocking ERa activity, which have already been proposed for use in the treatment of breast cancers in which BRCA1 or BRCA2 genes are mutated, due to its usual role in DNA repair (Bryant et al. 2005; Farmer et al. 2005).

Abbreviations

NR:

nuclear receptor

ERE:

estrogen response element

ChIP:

chromatin immunoprecipitation

HAT:

histone acetyltransferase

HDAC:

histone deacetyulase

HMT:

histone methyltransferase

SMRT:

silencing mediator of retinoid and thyroid receptors

NCoR:

nuclear receptor corepressor

AIB1:

amplified in breast cancer 1

EGF:

epidermal growth factor

HER-2/neu:

human epidermal growth factor receptor 2

IGF:

insulin-like growth factor

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