Ovarian toxicity of carboplatin and paclitaxel in mouse carriers of mutation in BRIP1 tumor suppressor gene

• Published in: Scientific reports 2022-02, Vol.12 (1), p.1658-13, Article 1658
• Main Authors: Ntemou, E., Vidal, P. Diaz, Alexandri, C., Van den Steen, G., Lambertini, M., Demeestere, I.
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; 631/67/1059/99; 631/67/1347; 692/163/2743/1526; Animals; Antineoplastic Agents, Phytogenic - administration & dosage; Antineoplastic Agents, Phytogenic - adverse effects; Apoptosis - drug effects; Apoptosis - genetics; BRCA1 protein; BRCA1 Protein - genetics; Breast cancer; Breast Neoplasms - genetics; Carboplatin; Carboplatin - administration & dosage; Carboplatin - adverse effects; Deoxyribonucleic acid; DNA; DNA Breaks, Double-Stranded - drug effects; DNA damage; DNA helicase; DNA repair; DNA Repair - drug effects; DNA Repair - genetics; Embryonic Development - drug effects; Embryonic Development - genetics; Fanconi Anemia Complementation Group Proteins - genetics; Female; Fertility; Fertilization in Vitro - methods; Genes; Genes, Tumor Suppressor; Germ-Line Mutation; Heterozygote; Heterozygotes; Humanities and Social Sciences; Infertility; Mice; Mice, Inbred C57BL; Mice, Knockout; Models, Animal; multidisciplinary; Mutation; Ovarian Follicle - drug effects; Ovarian Follicle - metabolism; Ovarian Reserve - drug effects; Ovaries; Paclitaxel; Paclitaxel - administration & dosage; Paclitaxel - adverse effects; Protein C; PTEN protein; RNA Helicases - genetics; Science; Science (multidisciplinary); Toxicity; Tumor suppressor genes; Tumors
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-022-05357-x

More than 10% of women diagnosed with breast cancer during reproductive age carry hereditary germline pathogenic variants in high-penetrance BRCA genes or in others genes involved in DNA repair mechanisms such as PALB2 , BRIP or ATM . Anticancer treatments may have an additional negative impact on the ovarian reserve and subsequently on the fertility of young patients carrying such mutations. Recently, the combination of carboplatin and paclitaxel is being recommended to these BRCA -mutated patients as neoadjuvant therapy. However, the impact on the ovary is unknown. Here, we investigated their effect of on the ovarian reserve using mice carriers of BRCA1-interacting protein C-terminal helicase-1 ( BRIP1 ) mutation that plays an important role in BRCA1 -dependent DNA repair. Results revealed that the administration of carboplatin or paclitaxel did not affect the ovarian reserve although increased DNA double-strand breaks were observed with carboplatin alone. Co-administration of carboplatin and paclitaxel resulted in a significant reduction of the ovarian reserve leading to a lower IVF performance, and an activation of the PI3K-Pten pathway, irrespective of the genetic background. This study suggests that co-administration of carboplatin and paclitaxel induces cumulative ovarian damage and infertility but a heterozygote genetic predisposition for DNA damage related to BRCA1 gene function does not increase this risk.