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

Autor:	Ntemou, E., Vidal, P. Diaz, Alexandri, C., Van den Steen, G., Lambertini, M., Demeestere, I.
Přispěvatelé:	Basic (bio-) Medical Sciences
Jazyk:	angličtina
Rok vydání:	2022
Předmět:	Heterozygote DNA Repair Paclitaxel endocrine system diseases Knockout Science Embryonic Development Antineoplastic Agents Apoptosis Breast Neoplasms Fertilization in Vitro Inbred C57BL Article Carboplatin Double-Stranded Mice Breast cancer Ovarian Follicle Models Phytogenic Chemotherapy Animals DNA Breaks Double-Stranded Genes Tumor Suppressor Ovarian Reserve Germ-Line Mutation Mice Knockout Multidisciplinary BRCA1 Protein Animal DNA Breaks Antineoplastic Agents Phytogenic Fanconi Anemia Complementation Group Proteins Female Mice Inbred C57BL Models Animal RNA Helicases female genital diseases and pregnancy complications Genes Gonadal disorders Medicine Tumor Suppressor
Zdroj:	Scientific Reports, Vol 12, Iss 1, Pp 1-13 (2022) Scientific Reports
ISSN:	2045-2322
Popis:	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.
Databáze:	OpenAIRE
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