BRCA1 haploinsufficiency impairs iron metabolism to promote chrysotile‐induced mesothelioma via ferroptosis resistance

Abstract

Malignant mesothelioma (MM) is still a social burden associated with asbestos exposure. Local iron accumulation thereby represents the major pathogenesis, followed by oxidative DNA strand breaks and genomic alterations in the mesothelium. BRCA1 is a critical component of homologous recombination repair directed to DNA double‐stranded breaks, whereas BRCA1 germline mutation is an established risk for breast/ovarian cancer, its role in MM development remains to be elucidated. Murine Brca1 mutant models so far have not reproduced human phenotypes. However, a rat Brca1 mutant model (Mut; L63X/+ ) recently reproduced them at least partially. Here we describe the differential induction of MM in Brca1 mutant rats by intraperitoneal injection of chrysotile or crocidolite. Only Mut males injected with chrysotile revealed a promotional effect on mesothelial carcinogenesis in comparison with wild‐type and/or females, with all the MMs Brca1 haploinsufficient. Array‐based comparative genomic hybridization of MMs disclosed a greater extent of chromosomal deletions in Brca1 mutants, including Cdkn2a/2b accompanied by Tfr2 amplification, in comparison with wild‐type tumors. Mutant MMs indicated iron metabolism dysregulation, such as an increase in catalytic Fe(II) and Ki67‐index as well as a decrease in Fe(III) and ferritin expression. Simultaneously, mutant MMs revealed ferroptosis resistance by upregulation of Slc7A11 and Gpx4. At an early carcinogenic stage of 4 weeks, induced Brca1 expression in mesothelial cells was significantly suppressed in chrysotile/Mut in comparison with crocidolite/Mut, whereas significant preference to iron with a decrease in Fe(III) has been already established. In conclusion, chrysotile exposure can be a higher risk for MM in BRCA1 mutant males, considering the rat results.

Environmental impact on carcinogenesis under BRCA1 haploinsufficiency

“…4). We recently obtained similar results on chrysotile-induced malignant mesothelioma by the use of male Brca1(L63X/ +) rats [90]. However, we still need to know the role of Brca1 haploinsufficiency in this mitochondrial damage and the demonstration in human BRCA1 mutant samples would be necessary.…”

The correlation of ferroptosis and DNA repair in individuals with colorectal cancer

“…FANCD2 and USP7 play critical roles in DNA repair pathways, and their aberrant expression may affect cellular responses to oxidative stress and susceptibility to ferroptosis (35)(36)(37)(38). CDKN2A is a tumor suppressor gene whose mutation or deletion may lead to the accumulation of DNA damage and reduced repair capacity (39,40). GSTM1, a member of the glutathione S-transferase family, is involved in intracellular REDOX reactions and detoxi cation processes, and its abnormal expression is linked to CRC occurrence and progression (41,42).…”

Targeted Therapy in Mesotheliomas: Uphill All the Way

“…PARP inhibition results in single-strand break accumulation that could become BSBs, which are lethal in HR repair-deficient cells [ 166 , 167 ]. BRCA1 (breast cancer susceptibility gene 1) and BRCA2 are tumor suppressor genes, and mutant phenotypes are predisposed to breast and ovarian cancers [ 168 ]. Even if the role of BRCA1 in MM remains to be elucidated, as both BAP1 and BRCA1 are involved in the DNA damage response, they can be considered biomarkers for targeted therapies with PARP inhibitors (PARPi).…”