Abstract 976: FOXA1 promotes a luminal growth program in prostate cancer

Abstract

Abstract FOXA1 is an important pioneering transcription factor for androgen receptor (AR), a key driver of prostate cancer. FOXA1 has emerged as one of the most recurrently mutated genes in primary and metastatic castrate resistant prostate cancer, with alterations frequencies ranging from 4-15% in various cohorts. Given the well-established role of FOXA1 in modulating AR function, we hypothesize that FOXA1 mutations contribute to prostate oncogenesis by altering the chromatin landscape, resulting in changes in the AR cistrome and AR transcriptional output. Here we use prostate organoids to show that acute FOXA1WT overexpression promotes lumen formation and drives luminal differentiation. Consistent with this, CRISPR/Cas9-mediated deletion of FOXA1 slows proliferation and organoids lacking FOXA1 fail to form lumens. Assays to evaluate the functionality of recurrent FOXA1 mutations (measured by cell viability, lumen formation, and lumen size) along with RNA-sequencing suggest there are distinct classes of FOXA1 mutations. The first are the gain-of-function mutations (such as FOXA1FE254-255del), which promote growth and lumen formation to a larger extent than wild-type FOXA1. Interestingly, a FOXA1 luciferase reporter assay we developed in HEK293 cells indicates that the majority of mutants tested behave as gain of function. The only mutant to score as loss of function, FOXA1R219S, is found nearly exclusively in prostate cancer, and is enriched in neuroendocrine prostate cancer cohorts. Expression of FOXA1R219S suppresses lumen formation and promotes both basal and epithelial-mesenchymal transition transcriptional programs. However, this mutant also provides a growth advantage beyond what is conferred by FOXA1WT. Taken together, these data suggest that FOXA1R219S is not simply a loss of function allele and instead may drive disease progression through a different set of signaling pathways than the FOXA1 alleles that promote luminal differentiation. Further study of these classes of mutations and how they relate to patient outcome, along with analysis of the FOXA1mut/AR cistromes, is ongoing to determine the genome-wide implications of FOXA1 alterations and how they promote prostate cancer progression. Citation Format: Elizabeth J. Adams, Elizabeth Hoover, Wouter R. Karthaus, Charles L. Sawyers. FOXA1 promotes a luminal growth program in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 976.