Abstract 787: Cytosolic TRIM24 characterizes an aggressive subset of ER- PR- and TP53 mutant breast cancer
Authors: Lalit R. Patel, Jurgen Mitsch, Grazziela P. Figueredo, Philip Quinlan, Lee B. Jordan, Colin A. Purdie, Savitri Krishnamurthy, Michelle C. Barton, Alastair M. Thompson
Journal: Cancer Research (2018)

Abstract Introduction: Tripartite Motif Containing 24 (TRIM24) is a PhD/Bromodomain containing steroid receptor co-activator that targets p53 for proteosomal degradation, transforms human mammary epithelial cells, and promotes treatment resistance in preclinical models. While bromodomain inhibitors and proteolysis targeting chimeras have been developed against TRIM24, the disease subtype it is most relevant to remains under explored. In this study, we characterize a uniquely annotated cohort of invasive ductal carcinomas for tumor expression of TRIM24 protein by immunohistochemistry (IHC) to assess its relationship with molecular and clinicopathological features. Methods: Tissue microarrays (TMAs) representing 198 tumors with 6 cores/tumor were obtained from the Tayside Biospecimen Repository and stained by IHC for TRIM24. TMAs were scored for nuclear and cytosolic intensity and the proportion of tumor cells with staining. These values were combined into Histo-scores (H-Scores) and averaged as a semi-quantitative metric for tumor TRIM24 expression. Statistical associations between TRIM24 H-Scores, clinicopathological annotations, and existing molecular profiles generated from the same TMA were determined using SciPy and SPSS. Results: TRIM24 has four distinct expression patterns in the 170 tumors with scorable cores on the TMA: nuclear (55), cytosolic (38), nuclear and cytosolic (35), and negative (42). Non-parametric analysis revealed associations between TRIM24 expression pattern and ER (χ2=21.3, p=0.000), PR (χ2=14.8, p=0.002), invasive grade (χ2=14.9, p=0.021), and TP53 mutation (χ2=9.55, p=0.023). No significant association was found with HER2 (χ2=1.51, p=0.68). Higher nuclear H-scores are observed in ER+ (p=0.0008) and PR+ (p=0.001) tumors. Higher cytosolic but not nuclear H-scores are observed in Grade 3 (p=0.003), triple negative (TNBC, p=0.004), and TP53 mutant (p=0.0289) cases. Kaplan-Meier analysis revealed high cytosolic (p=0.037) but not nuclear (p=0.601) H-scores associated with poor survival in ER- patients. No significant survival difference was found in ER+ patients stratified by nuclear (p=0.781) or cytosolic (p=0.683) H-scores. Similar analysis of TNBC was underpowered. TP53 mutant (p=0.142) but not TP53 wild type (p=0.378) disease with high cytosolic H-scores trend toward diminished survival. No such trend is observed in cases stratified by nuclear H-scores and TP53 status. Conclusions: TRIM24 is overexpressed in most human breast cancers. Nuclear expression is more common in ER+/PR+ tumors but does not stratify outcome. Cytosolic expression occurs in Grade 3, ER-, and TP53 mutant tumors and associates with poor clinical outcome in ER- disease. This suggests TRIM24 may be a more relevant drug target in ER-/PR- than luminal breast cancer and emphasizes the need for studies investigating the cytosolic functions of TRIM24 in ER-/PR- and TP53-mutant breast cancer. Citation Format: Lalit R. Patel, Jurgen Mitsch, Grazziela P. Figueredo, Philip Quinlan, Lee B. Jordan, Colin A. Purdie, Savitri Krishnamurthy, Michelle C. Barton, Alastair M. Thompson. Cytosolic TRIM24 characterizes an aggressive subset of ER- PR- and TP53 mutant breast 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 787.