The tumor suppressor BRCA1 protein has been implicated in hereditary breast and ovarian cancer syndrome when its gene is mutated. Among the many functions of BRCA1 including DNA repair, transcriptional regulation, cell cycle checkpoint, apoptosis, chromatin remodeling, and centrosome replication, DNA double-strand breaks repair by homologous recombination (HR) is one of the most important. BRCA1-associated tumors increase DNA instability and become sensitive to the Poly (ADP-ribose) polymerase (PARP) inhibitor. It is well known that PTEN-induced kinase 1 (PINK1) and Parkin are involved in mitochondrial quality control and a variety of mutations in these genes causes early-onset Parkinson's disease. In the present study, we report a novel degradation mechanism for BRCA1 protein in response to mitochondrial damage.
While investigating the role of BRCA1 in mitophagy using a breast cancer cell line, we found that BRCA1 protein is rapidly degraded by the mitochondrial targeting reagents, which induce mitochondrial depolarization. The degradation was mediated by the ubiquitin-proteasome system through the direct interaction with the E3 ligase Parkin upon PINK1 upregulation in response to the mitochondrial damage. Moreover, BRCA1 knockdown repressed cancer cell growth. Immunostaining the specimens from breast cancer patients revealed higher BRCA1 and lower PINK1/Parkin expression in their mammary glands. This result correlates with the analysis using the mRNA expression data set from TCGA database. Additionally, BRCA1 expression inversely correlated with PINK1/Parkin expression in the case of relapse-free survival in breast cancer patients. Thus, these findings demonstrated the unanticipated physiological functions of BRCA1 for maintaining cancer cell growth.
Overall, our study shows that: 1) Degradation of BRCA1 due to PINK1-Parkin activity through the ubiquitin-proteasome system occurs in response to mitochondrial damage. 2) BRCA1 promotes the growth of breast cancer cells. 3) Immunostaining of patient specimens and cancer genome data set analysis revealed higher BRCA1 expression with lower PINK1/Parkin expression was observed in the cancerous mammary glands. Moreover, recent reports have suggested that BRCA1 is involved in the pathogenesis of Alzheimer's disease. Thus, transmission of mitochondrial damage to the nucleus causing nuclear DNA double-strand breaks via the PINK1-Parkin-BRCA1 axis may not only be seen in the field of oncology, but also in various other fields including neurodegenerative diseases.
Citation Format: Kana Miyahara, Naoharu Takano, Yumiko Yamada, Hiromi Kazama, Mayumi Tokuhisa, Hirotsugu Hino, Koji Fujita, Edward Barroga, Masaki Hiramoto, Hiroshi Handa, Masahiko Kuroda, Takashi Ishikawa, Keisuke Miyazawa. BRCA1 degradation in response to mitochondrial damage in breast cancer cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 296.