Abstract 2051: MDN1, a novel potential early biomarker for endocrine resistant breast cancer

Abstract

Abstract Midasin (MDN1) is a chaperone protein required for maturation and nuclear export of pre-ribosomal RNA. Recent investigation regarding the mutational status of MDN1 in breast cancer (BC) revealed an increased tumor mutational burden in BC patients. Interestingly, our previously published work demonstrated significantly high MDN1 protein levels in AI-resistant mammospheres. Therefore, we investigated the overall status of MDN1 in the TCGA database in breast cancer tumors and identified MDN1 expression in breast cancer cells that were sensitive or resistant to AIs. The purpose of this study was to evaluate whether there is an association between MDN1 expression or mutation status to examine if MDN1 functions as an early high-risk indicator for breast cancers resistant to AIs or endocrine therapy. Using the cBioportal for Cancer Genomics, in silico analysis was conducted and BC patients with altered MDN1 status demonstrated several clinical attributes that were significantly associated with higher mutation counts (Kruskal Wallis test, p value = 1.41 × 10-10 and q value = 4.11 × 10-9); MSI sensor score, (p value = 2.74 × 10-5 and q value = 2.27 × 10-4); and Fraction Altered Genome score (p value = 2.37 × 10-3 and q value = 0.011). Next, aneuploidy in breast cancer significantly evolved and was positively correlated with higher MDN1 expression (Spearman: 0.64, p value = 3.92 × 10-122). Compared to the other BC subtypes, MDN1 was significantly elevated in basal breast cancer (Chi square test p value < 10.0 × 10-10, q value = 4.11 × 10-9) and significantly higher in deceased versus living BC patients. The DepMap breast cancer cell line database analysis also revealed significantly increased MDN1 expression in both ER+/HER2- cell lines (p value = 7.93 × 10-3; 12 cell lines) and in ER-/HER2- cell lines (p value = 2.88 × 10-2; 31 cell lines). Primary and metastatic BC cell lines were compared and MDN1 expression was significantly higher in metastatic BC cells (p value = 8.04 × 10-5; 33 metastatic cell lines). Likewise, AI-resistant cell lines exhibited altered MDN1 expression compared to their sensitive counterparts. Additionally, there was a statistically significant association between higher ER copy number and increased MDN1 expression in BC cell lines (p value = 1.44 × 10-3; 61 cell lines). Further in-depth analysis of proteins that were coexpressed in MDN1-altered tumors revealed a panel of genes (MSH2, MSH6, RBM15, FOXM1,CCNE2, and CHEK1) that could represent a signature of early markers of AI-resistant BC since there was a positive correlation between MDN1 expression and associated pathways. In conclusion, increased expression of MDN1 in BC tumors or cells may serve as preliminary marker to predict resistance to endocrine therapy due to its significant association with genes such as MSH2, MSH6 and FOXM1 that are strongly established as indicators of endocrine resistance. This work was supported by NIH grant # SC1GM126617 and U54MD007582. Citation Format: Afia Ohemeng, Akash Gupta, Bipika Banjara, Mounika M. Pamukuntla, Manasa Kotina, A Michael Davidson, Syreeta L. Tilghman. MDN1, a novel potential early biomarker for endocrine resistant breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2051.