Sumo-Modified Androgen Receptors Support The Metastatic Phenotype Of Endocrine-Resistant Hormone Receptor-Positive Breast Cancer

Background: Conventional endocrine therapy is the first-line treatment for hormone receptor positive (HR+) breast cancer (BCa) subtype. Frequently, intrinsic and acquired ET resistance (ET-R) persists to support a disease with poor prognosis and limited therapy than the ET-sensitive carcinoma. High levels of androgen receptors (AR) in HR+ BCa correlate with insensitivity to ET tamoxifen and greater susceptibility to cancer metastasis. However, targeting AR with antagonist enzalutamide (Enz) in ET-R HR+ BCa present conflicting results. In the current report, we present novel findings of a constitutively active modified AR population that accumulates in the ET-R HR+ BCa cells to drive cell migration and metastatic phenotype. Methods: Cell-free protein modification tests, in-house SUMOylation assays, and PLA imaging were used to determine the AR protein profile in multiple ET-sensitive, intrinsic-, and acquired-ET HR+-BCa lines. Reporter assay and targeted transcriptome studies evaluate the genomic activity of native and modified-AR mimetic. Finally, the inhibitory effect of Enz with or without combination therapy was determined using migration and spheroid growth studies. Results: In acquired and intrinsic ET-R BCa cell lines, a constitutively active, higher molecular weight SUMO-modified AR (SUMO-AR) persists at the chromatin. The SUMO-AR is resilient to ubiquitin-mediated proteasomal degradation. We now report that the canonical AR chaperone protein HSPB1/Hsp27 functions as a novel SUMO-E3 ligase for AR. SUMO-AR interacts with a unique repertoire of biomolecules as compared to unmodified AR in the same cell lines. An increase in the SUMO protein and global SUMO-modified proteome supports this multimeric complex. The ligand-independent SUMO-AR activity promotes a gene-expression profile that favors epithelial-mesenchymal transition. Treatment with Enz alone or in combination with a SUMO inhibitor attenuates migration and metastatic phenotype of ET-R HR+ BCa. Conclusion: SUMO-AR dictates metastatic susceptibility and Enz responsiveness of ET-R HR+ BCa. Consistently, targeting both unmodified and SUMO-modified AR serves as a better therapeutic strategy for advanced HR+ BCa. Citation Format: Tasneem Bawa-Khalfe, Shaymaa Bahnassy, Hariprasad Thangavel, Maram Quttina, Ashfia Fatima Khan, Dhanya Dhanyalayam, Joan Ritho, Samaneh Karami, Jing Ren. Sumo-modified androgen receptors support the metastatic phenotype of endocrine-resistant hormone receptor-positive breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS17-33.