Abstract P5-09-03: Mieap, a p53-downstream gene, is associated with suppression of breast cancer cell proliferation and better survival
Authors: Futamura Manabu , Tokumaru Yoshihisa , Takabe Kazuaki , Arakawa Hirofumi , Yoshida Kazuhiro 
Published: March 2022

Abstract
(Introduction) We previously reported that the mitochondria-eating protein (Mieap), a p53-downstream gene, is involved in mitochondrial quality control (MQC) by repairing or eliminating unhealthy mitochondria. In the breast mass, endogenous cytoplasmic Mieap was detected in 32% of invasive ductal carcinomas (IDCs), 55.6% of ductal carcinomas in situ, and 88.9% of fibroadenomas by immunohistochemistry (IHC). We also demonstrated that the p53/Mieap-regulated MQC pathway was inactivated in 26.1% of IDCs, wherein its impairment resulted in a significantly shorter disease-free survival (DFS) of patients with primary breast cancer. Therefore, in the present study, we aimed to characterize Mieap as a tumor suppressor and determine its association with prognosis using large human breast cancer cohorts. (Materials and methods) We identified 2980 patients from two worldwide large-scale primary breast cancer cohorts: The Cancer Genome Atlas (TCGA; n=1076) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC; n=1904). Mieap expression and survival data were extracted using the cBioPortal and Broad Institute Firehose websites. Regarding the ER+/HER2- (luminal), HER2+, and ER-/HER2- (triple negative; TN) breast cancer subtypes, 1336, 236, and 267 patients from the METABRIC cohort were found to have the respective subtypes, whereas from the TCGA cohort, 584, 182, and 157 patients had the respective subtypes. We then divided patients into the high and low groups on the basis of median gene expression levels in each cohort and analyzed the association between Mieap expression and clinical outcome. The Kaplan-Meier method was used to compare the survival curves between Mieap-high and Mieap-low groups, and Fisher’s exact test was performed to compare the clinicopathological characteristics for significance. Furthermore, expression of Mieap-associated genes was evaluated by Gene Set Enrichment Analysis (GSEA). (Results) Mieap expression was significantly downregulated in tumors than in normal tissues in TCGA. It was significantly downregulated in p53-mutant tumors in the whole cohort, and in all luminal, HER2+, and TN subtypes of both cohorts, indicating that Mieap expression was dependent on p53 status. Furthermore, BNIP3 and NIX, co-factors of Mieap, were downregulated in tumors than in normal tissues in TCGA. These expressions were positively correlated with Mieap expression. GSEA demonstrated that cell cycle- and proliferation-associated gene sets (Myc Targets, E2F targets, G2M checkpoint, Mitotic spindle etc.) were significantly enriched in Mieap-low tumors than in Mieap-high tumors. Mieap expression was significantly correlated with KI67, a cell proliferation marker. Mitochondria-associated gene sets were enriched in Mieap-high tumors. Mieap was found to be downregulated in advanced cancer stage and/or histological grade consistently in both cohorts. Mieap expression was downregulated in metastatic tumors than in primary tumors. In the METABRIC cohort, we found that the DFS and overall survival of patients with Mieap-high tumors were significantly longer than those of patients with Mieap-low tumors among those with the whole and luminal subtypes. Similarly, in the TCGA cohort, the DFS of patients with Mieap-high tumors was longer among those with the luminal subtype. (Conclusion) In conclusion, we found that the mechanistic role of Mieap was clinically relevant in the two independent cohorts. Specifically, Mieap was found to be p53-dependent, and its downregulation was associated with advanced breast tumors. Moreover, Mieap-high tumors demonstrated favorable breast cancer prognosis, particularly in the luminal subtype, because of Mieap’s control over the cell cycle. Thus, Mieap plays an important role as a tumor suppressor in breast cancer.
Citation Format: Manabu Futamura, Yoshihisa Tokumaru, Kazuaki Takabe, Hirofumi Arakawa, Kazuhiro Yoshida. Mieap, a p53-downstream gene, is associated with suppression of breast cancer cell proliferation and better survival [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-09-03.