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Evaluating the Impact of FOXA1 Mutations on the AR Transcriptional Program in Castration-Resistant Prostate Cancer


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Forkhead box A1 (FOXA1) is a pioneer transcription factor that is essential for the normal development of several endoderm-derived organs, including the prostate gland. FOXA1 is frequently mutated in the hormone-receptor driven prostate, breast, bladder, and salivary gland tumor. However, how FOXA1 alterations affect cancer development is unclear, with FOXA1 previously ascribed both tumor suppressive and oncogenic roles. Here we assemble an aggregate cohort of 1546 prostate cancers (PCa) and show that FOXA1 alterations fall into three distinct structural classes that diverge in clinical incidence and genetic co-alteration profiles, with a collective prevalence of 35%. Class1 activating mutations originate in early PCa without ETS or SPOP alterations, selectively recur within the Wing2-region of the DNA-binding Forkhead domain (FKHD), enable enhanced chromatin mobility and binding frequency, and strongly transactivate a luminal androgen receptor (AR) program of oncogenesis. By contrast, class2 activating mutations are acquired in metastatic PCa, truncate the C-terminal domain of FOXA1, enable dominant chromatin binding, and through TLE3 inactivation promote WNT-pathway driven metastasis. Finally, class3 genomic rearrangements are comprised of duplications and translocations within the FOXA1locus, and structurally reposition a conserved regulatory element, the FOXA1 Mastermind (FOXMIND), to drive overexpression of FOXA1 or other oncogenes. Our study reaffirms the central role of FOXA1 in mediating AR-driven oncogenesis, and provides mechanistic insights into how different classes of FOXA1 alterations uniquely promote PCa initiation and/or metastatic progression. Furthermore, these results have direct implications in understanding the biology of other hormone-receptor driven cancers and rationalize therapeutic co-targeting of FOXA1 activity.



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