Wilbert Zwart Group
Our research is focused on translational endocrinology and all our projects revolve around steroid hormone receptors. As major fields of interest, we study the response to therapeutic interventions in breast and prostate cancer. For both tumor types, multiple hormonal therapeutics are clinically available, and there is a clear need for treatment-selective biomarkers to achieve tailored therapy. Over recent years, we found numerous coregulators of estrogen receptor α (ERα) to play causal roles in treatment response and patient outcome, including RIP140, USP9X, VAV3 and ATF-2. Since many of these proteins have their own distinct chromatin binding signatures and directly affect ER function, downstream gene expression profiles may be affected. Based on the genome-wide chromatin binding landscapes of ATF-2, RIP140, SRC3, CBP and USP9X, we identified predictive and prognostic gene expression signatures that can stratify breast cancer patients on outcome after hormonal treatment.
In human breast tumors, we mapped the genome-wide chromatin-binding profiles of most steroid hormone receptors (ERα, Progesterone Receptor, Androgen Receptor, Glucocorticoid Receptor), their direct interaction partners (FOXA1, GATA3) as well as multiple histone modifications (H3K4me3, H3K4me1, H3K27me3). These findings enabled us to further refine prognostic biomarkers and to identify patient subpopulations with differential response to hormonal therapeutics in the metastatic setting. Interestingly, most steroid hormone receptors converge in their genomic actions, with the vast majority of chromatin binding sites shared between them. These findings implicate extensive genomic crosstalk between all steroid hormone receptors in human breast tissue, with direct clinical implications.
To identify prognostic markers and to identify causal players in prostate cancer progression, we determined Androgen Receptor (AR) protein complex composition and the deviations thereof on a genome-wide scale. We found tumors with acquired resistance to androgen deprivation therapy to possess distinct AR chromatin binding profiles as compared to treatment sensitive tissue specimens. Changes in AR chromatin interactions between tumors enabled the identification of a distinct gene signature with strong prognostic potential in primary prostate cancer patients. With this, we presented a concise and reproducible gene expression signature that enables the identification of prostate cancer patients with low-risk of relapse versus patients with high-risk of relapse and who may therefore benefit from androgen deprivation therapy in the adjuvant setting.