Estrogen signalling

Aim of this research line is to unveil the mechanism by which steroid hormones and endocrine drugs, such as tamoxifen, exert their actions. Understanding these mechanisms is important to improve drug efficacy, to tailor their use to responsive patients and to predict side effects of novel drugs.

Estrogens are natural mitogenic factors in gynaecological tissues and exposure to exogenous (hormone-replacement-therapy or adjuvant breast cancer therapy) or endogenous estrogens (high BMI, aberrant estrogen signalling or aberrant expression of steroid converting enzymes) leads to unbalanced growth and to gynaecological disorders and cancers.

All major actions of estrogens are mediated by the estrogen receptor-alpha (ER-alpha). ER-alpha is a ligand-dependent transcription factor. Its activity on gene transcription is modulated and fine-tuned by co-regulators, proteins that bridge (co-activators) or impair (co-repressors) the ER-alpha /target-promoter complexes with the transcriptional machinery. The current view suggests that upon binding to Estrogen Response Elements (EREs) or other motifs in the promoter of target genes, ER-alpha recruits co-regulatory proteins at target genes and mediates activation of transcription or its repression. Distinct transcriptional activities on distinct target genes in one cell type are determined by recruitment of different co-regulators.

Moreover, several compounds, such as tamoxifen, show anti-estrogenic action in some tissues (like breast) and at the same time they have estrogenic action in other tissues (such as the endometrium). These opposite effects are determined by the fact that the transcription of the same target genes is modulated in opposite directions in different tissues. These events are also a consequence of the fact that tamoxifen-bound ER-alpha recruits co-regulators with opposite activities in different tissues.

For instance, a number of genes, such as BCL2L1, are modulated in opposite directions in breast (transcription up-regulation) and endometrial (down-regulation) cell lines. Tamoxifen-bound ER-alpha recruits co-activators to the BCL2L1 promoter  in breast cells leading to transcription activation, whereas co-repressors are recruited in endometrial cells with subsequent inhibition of transcription. These transcriptional effects can be either opposed or inverted by modifying the level of some co-regulators. 

By means of molecular analyses including cDNA-microarrays and chromatin-immunoprecipitation/ chip promoter array (ChIP-chip), and by means of bioinformatics tools (in collaboration with the Department of Bioinformatics-BiGCaT, Maastricht University), we investigate the mechanism of action of ER-alpha and the role of co-regulators in determining the tissue-and the gene-specific responses to estrogens.

These mechanisms are often the cause of the side effects observed during the use of endocrine drugs, or are the cause of the resistance of tumours to endocrine drugs. A thorough understanding of the mechanisms behind these events helps predicting therapeutic efficacy in patients, tailoring therapies to responsive patients and predicting side effects of novel drugs.

Selected publications
Romano A et al. Mol Cell Endocrinol. 2010 314:10-100.
Punyadeera C et al. J Steroid Biochem Mol Biol. 2008 112(1-3):102-9.
Groothuis PG et al. Hum Reprod Update. 2007 13(4):405-17
Dassen H et al. Cell Mol Life Sci. 2007 64(7-8):1009-32.
Punyadeera C et al. Cell Mol Life Sci. 2005 62(2):239-50.