Kaseki Satoshi, Sonehara Reina, Motooka Yashiro, Tanaka Hideaki, Nakamura Tomoko, Osuka Satoko, Akatsuka Shinya, Kajiyama Hiroaki, Mashimo Tomoji, Imaoka Tatsuhiko, Toyokuni Shinya
Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Cancer Sci. 2025 Apr;116(4):1139-1152. doi: 10.1111/cas.16412. Epub 2025 Feb 3.
BRCA1 is one of the causative genes for hereditary breast and ovarian cancer syndrome with a high risk of early-onset breast cancer. Whereas olaparib (OLA), an inhibitor of poly-ADP-ribose polymerase, has been applied as adjuvant therapy to those cancer patients, its effect on ovarian reproductive function remains unelucidated. Recently, a rat model (MUT; Brca1 mutation) mimicking a human BRCA1 pathogenic variant has been established. Using this model, we evaluated the effects of OLA on ovarian reproductive function in comparison with the wild-type (WT) rats. MUT showed a significantly reduced number of primordial follicles and subfertility in accordance with aging. Oxidative stress was significantly elevated in the young MUT granulosa cells (GCs) accompanied by increased mTOR but decreased PTEN signals. OLA administration in MUT further decreased primordial follicles, with gene set enrichment analysis, indicating upregulated DNA repair pathways. Furthermore, a combination of OLA and cyclophosphamide (CPA) induced empty primordial follicles, recognized as CPA-induced severe ovarian toxicity. Whereas OLA + CPA caused greater reduction in primordial follicles both in MUT and WT in comparison with CPA alone, MUT ovaries were more susceptible to oxidative stress, potentially depleting primordial follicles via activation of GCs and inducing oocyte death due to accumulated DNA damage by OLA treatment. Our findings in this preclinical model underscore the importance of evaluating ovarian reserve prior to chemotherapy by performing reproductive consultation with female patients with BRCA1 pathogenic variants.
BRCA1是遗传性乳腺癌和卵巢癌综合征的致病基因之一，与早发性乳腺癌的高风险相关。聚腺苷酸二磷酸核糖聚合酶抑制剂奥拉帕利（OLA）已被用作这些癌症患者的辅助治疗，但其对卵巢生殖功能的影响仍不明确。最近，已建立了一种模拟人类BRCA1致病变体的大鼠模型（MUT；Brca1突变）。利用该模型，我们评估了OLA与野生型（WT）大鼠相比对卵巢生殖功能的影响。随着年龄增长，MUT的原始卵泡数量显著减少且生育力低下。年轻MUT颗粒细胞（GCs）中的氧化应激显著升高，同时mTOR增加但PTEN信号降低。MUT中给予OLA进一步减少了原始卵泡，基因集富集分析表明DNA修复途径上调。此外，OLA与环磷酰胺（CPA）联合使用会诱导空的原始卵泡，这被认为是CPA诱导的严重卵巢毒性。与单独使用CPA相比，OLA + CPA使MUT和WT的原始卵泡减少更多，MUT卵巢对氧化应激更敏感，可能通过激活GCs消耗原始卵泡，并因OLA治疗导致的DNA损伤积累而诱导卵母细胞死亡。我们在这个临床前模型中的发现强调了在对携带BRCA1致病变体的女性患者进行化疗之前，通过进行生殖咨询来评估卵巢储备的重要性。
