Abstract 7468: Androgen response and prognostication in luminal androgen receptor-positive TNBC patients: Defining a novel signature
Authors: Osama Mustafa Younis, Jehad Amer Yasin, Afaf Mansour, Mohammad Abdulla, Dana Alsafadi, Mamoun Ahram
Journal: Cancer Research (2025)

Abstract Triple negative breast cancer (TNBC) is an aggressive form of cancer that has been subclassified into six molecular subtypes. One subtype, the luminal androgen receptor (LAR), which is characterized by over-expression of the androgen receptor (AR), confers the worst survival. In this work, we aimed to elucidate the androgen-regulated expression profile and molecular pathways involved in the survival of LAR patients. Microarray and bioinformatic analyses of gene expression and microRNA (miRNA) levels were performed following treatment of MDA-MB-453 cells with 10 nM dihydrotestosterone (DHT) for 48 hours. Differentially expressed genes were overlapped with GSE245554, which treated MDA-MB-453 cells with a selective androgen receptor degrader. Overlapped genes with opposing expression patterns were considered androgen-dependent. Shortlisted genes were run through univariate, multivariate, and Kaplan-Meier-based signature collection using the METABRIC cohort. Validation was conducted across the KMplotter and TCGA cohorts. Finally, gene set enrichment analysis (GSEA) between high and low signature expression was carried out using enrichr, and miRNA-mRNA interactions were identified through multiMiR. An 11 gene signature involving FASN, CYFIP2, HSD11B2, EPS8, DALRD3, NANS, MGAT4A, LRRN1, SPATA13, SSR1, and GPCPD1 (LARsig) was curated. LARsig was prognostically significant in the TNBC and LAR cohorts using overall survival (OS) and recurrence-free survival (RFS) metrics. In the high LARsig cohort, LAR patients had a median RFS of 40 months, in comparison to 120 months of the low LARsig cohort (HR = 2.37, 95% CI: 1.39-4.04, p &amp;lt; 0.01). A Cox regression-based risk score was inserted into a multivariate Cox model with age, grade, and tumor stage which revealed a consistent OS prognostic significance (HR = 2.41, 95% CI: 1.30-4.49, p &amp;lt; 0.01). GSEA showed an immunosuppressive environment where downregulated genes had terms like TNF-alpha signaling, IFN-gamma signaling, apoptotic processes, and cellular defense response. Upregulated genes showed terms consistent with stress response such as macromolecule catabolic process, autophagy, cell cycle, macro-autophagy, and negative regulation of apoptosis. Lastly, FASN appears to play the biggest biological role in our signature. Six differentially expressed miRNAs had validated interactions with FASN including miR-20b-3p (Fold Change = 3.36, FDR p value = 0.0132). MiR-20b-3p had positive co-expression (R = 0.19, p = 0.01) with FASN in the TCGA TNBC cohort. Overall, our study presents the first androgen response signature in LAR patients, and elucidates the possible mechanisms underlying patient survival and treatment resistance. Employment of our risk score for patient stratification in future androgen blockade-based trials could be of clinical utility. Citation Format: Osama Mustafa Younis, Jehad Amer Yasin, Afaf Mansour, Mohammad Abdulla, Dana Alsafadi, Mamoun Ahram. Androgen response and prognostication in luminal androgen receptor-positive TNBC patients: Defining a novel signature [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 7468.