Witteke B.R. Dekker1,2, Tesa M. Severson1,2, Shivakumar Keerthikumar3,4,5, Nicholas Choo3, Mitchell G. Lawrence3,4,5,6,7,Andries M. Bergman1,2,8#, Wilbert Zwart1,2,8,9 #
1 Division of Oncogenomics, The Netherlands Cancer Institute, Amsterdam, The Netherlands
2 Oncode Institute, The Netherlands.
3 Department of Anatomy and Developmental Biology, Biomedicine Discovery Institute, Monash University, Clayton, Australia
4 Peter MacCallum Cancer Centre, Melbourne, Australia
5 Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Australia
6 Cabrini Institute, Cabrini Health, Malvern, Australia
7 Melbourne Urological Research Alliance, Monash University, Clayton, Australia
8 Division of Medical Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
9 Department of Biomedical Engineering, Eindhoven University of Technology, 5600 MB Eindhoven, The Netherlands.
# Co-corresponding authors
The androgen receptor (AR) and estrogen receptor α (ERα) are key regulators in prostate cancer and breast cancer, respectively. Interestingly, in estrogen receptor-positive breast cancer, AR acts as a tumour suppressor, while in prostate cancer (PCa), ERα shows more oncogenic signals. Recent studies suggest that ERα contributes to prostate cancer progression. In particular, ERα is implicated in the progression of prostate adenocarcinoma to neuroendocrine prostate cancer (NEPC), a highly aggressive and treatment-resistant subtype. In NEPC patient-derived xenografts (PDXs), we observed higher ERα expression compared with treatment-naïve metastatic PCa and primary PCa samples. These findings suggest that ERα promotes the progression of PCa adenocarcinoma to NEPC. We hypothesize that during PCa progression, some prostate tumors shift from an AR-driven to an ERα-driven transcriptional program, thereby facilitating NEPC development. To test this hypothesis, we will use ERα-expressing NEPC cell lines and PDX models, combined with functional genomic approaches, to identify where ERα binds to the genome and determine the genes regulated by ERα. Furthermore, we will also be studying binding partners of ERα to better understand its molecular function. Lastly, we will study the effects of androgen deprivation therapy (ADT) on ERα expression, both in patient-derived model systems as well as in patient cohorts, to determine the dynamic action of ERα levels and activity upon ADT.