Abstract 3825: Divergent evolution of FOXA1 mutations drive prostate tumorigenesis or therapy-resistant intra-luminal plasticity
Authors: Sanjana Eyunni, Rahul Mannan, Yuping Zhang, Eleanor Young, Jie Luo, Jean Ching-Yi Tien, Qiuyang Zhang, Matthew Pang, Somnath Mahapatra, James George, Mustapha Jaber, Hamzah Hakkani, Sandra Carson, Abbey Todd, Noshad Hosseini, Ryan Rebernick, Xuhong Cao, Rui Wang, Fengyun Su, Rohit Mehra, Marcin Cieslik, Arul Chinnaiyan, Abhijit Parolia
Journal: Cancer Research (2025)

Abstract Androgen receptor (AR) signaling is critical for the survival and proliferation of prostate cancer (PCa) cells, thus making androgen deprivation therapy (ADT; e.g., castration) the mainstay for treatment. Notably, the oncogenic transcriptional functions of AR rely on a host of chromatin-binding regulatory proteins, which includes a pioneer transcription factor called FOXA1. FOXA1 de-compacts chromatin to enable DNA binding of AR and activation of target gene expression. Our lab found FOXA1 alterations to recur within three distinct structural classes in over 35% of metastatic castration-resistant PCa (mCRPC) cases in Caucasian White men. Subsequent studies reported FOXA1 mutations to be prevalent in over 40% of primary PCa in Chinese patients, thus positioning FOXA1 as a principal oncogene in this disease. Yet, the tumorigenic potential and pathobiology of FOXA1 alterations remain unexplored in vivo. Here, we have developed and characterized the first in-field transgenic mouse models that conditionally overexpress FOXA1 mutants in the prostate luminal epithelia. Our findings reveal that FOXA1 class1 mutations (i.e., wing 2 alterations) in a Trp53-null background drive high-grade, invasive luminal prostate adenocarcinoma with complete penetrance by 40 weeks. These lesions retain cardinal luminal features of the human disease, including regression upon androgen withdrawal. Mechanistically, the Class1 mutants reprogram AR and activate the PI3K/mTORC1 pathway to drive transformation. In contrast, FOXA1 class 2 mutations (i.e., C-terminal truncations) that are acquired in human mCRPC do not drive prostate luminal transformation in mice. Instead, these mutations induce intra-luminal plasticity by reprogramming differentiated cells into a progenitor stem-like state within androgen-replete normal tissues—a phenomenon otherwise induced upon castration. Class2 mutants lead to a 20-fold expansion of Ar+/Ck8+ luminal epithelia that gain expression of stemness markers such as Trop2, Ck4, and Psca. Mechanistically, we found the cistromically-dominant Class2 mutants to pioneer over 40, 000 neo-enhancer elements, bound by stemness-associated transcription factors, which instructed an androgen-insensitive luminal progenitor cell fate. Consistently, we found Class2-mutant mouse prostates to show minimal atrophy upon castration, with immunohistological assessment uncovering a higher density of Ki67+ luminal epithelial cells relative to both wild-type and Class1-mutant tissues. Collectively, our data establishes FOXA1 as a multifaceted oncogene in AR-dependent prostate cancers, wherein divergent evolution of FOXA1 mutational classes distinctly drive either cancer formation or therapy-resistant, intra-luminal plasticity during disease progression. These findings also represent the first report of FOXA1-driven prostate adenocarcinoma in mice. Citation Format: Sanjana Eyunni, Rahul Mannan, Yuping Zhang, Eleanor Young, Jie Luo, Jean Ching-Yi Tien, Qiuyang Zhang, Matthew Pang, Somnath Mahapatra, James George, Mustapha Jaber, Hamzah Hakkani, Sandra Carson, Abbey Todd, Noshad Hosseini, Ryan Rebernick, Xuhong Cao, Rui Wang, Fengyun Su, Rohit Mehra, Marcin Cieslik, Arul Chinnaiyan, Abhijit Parolia. Divergent evolution of FOXA1 mutations drive prostate tumorigenesis or therapy-resistant intra-luminal plasticity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3825.