Project description:Premature ovarian insufficiency (POI) is defined as a primary ovarian defect characterized by absent menarche (primary amenorrhea) or premature depletion of ovarian follicles before the age of 40 (secondary amenorrhea) with hypergonadotropism and hypoestrogenism. Premature ovarian insufficiency has few known genetic causes but in familial cases a genetic link is often suspected. A large consanguineous family with three female affected with POI was investigated. All samples including 3 affected and 5 unaffecd underwent whole genome SNP genotyping using Affymetric Axiom_GW_Hu_SNP array. Linkage analysis was carried out using HomozygosityMapper and Allegro softwares.Linkage analysis mapped the disease phenotype to long arm of chromosome 20. Sequence data analysis of potential candidate genes failed to detect any pathogenic variant.
Project description:<p>BRCA1 mutations are a hallmark of hereditary ovarian cancer, strongly linked to deficiencies in homologous recombination (HR) DNA repair and impaired DNA replication fork protection. However, its roles in cancer progression beyond maintaining genomic integrity remain poorly understood. Through metabolomics approaches, we found BRCA1-deficiency strikingly increased choline metabolism. Loss of BRCA1 promotes choline uptake through upregulating choline transporter-like protein 4 (CTL4). BRCA1 directly binds and recruits EZH2-mediated H3K27Me3 deposition to CTL4 promoter. CTL4 was therefore overexpressed in ovarian cancer tissues with BRCA1 mutations. Furthermore, BRCA1-deficiency significantly promotes ovarian cancer invasion, while inhibition of CTL4 reverses the high metastatic potential of BRCA1-deficient ovarian cancer cells, suggesting the functionality and specificity of CTL4 as a therapeutic target. Additionally, we discovered that phosphocholine, the choline metabolite increased by CTL4 overexpression, interacted with and stabilized the epithelial-to-mesenchymal transition inducer FAM3C in BRCA1-deficient ovarian cancer cells. Importantly, we identified a potent CTL4 inhibitor, DT-13, which significantly reduces choline metabolism and effectively suppresses metastasis in BRCA1-deficient ovarian cancers. Therefore, our study uncovers a mechanism underlying metastasis in BRCA1-deficient cancers and identifies CTL4 as a therapeutic target for metastatic ovarian cancer patients with BRCA1 mutations.</p>
Project description:Primary ovarian insufficiency (POI) and related infertility, early menopause, and endocrine disorders are major side effects in young female cancer patients undergoing cancer treatment. Current strategies preserving ovarian functions and fertility can be suboptimal due to concerns of feasibility, efficacy, or safety. Herein, we identify c-Jun N-terminal kinase (JNK) as a pivotal factor regulating the DNA damage response (DDR) signaling in oocytes of primordial follicles in response to DNA-damaging chemotherapy. Using pharmacological inhibition of JNK and a mouse model with oocyte-specific deletion of JNK, together with bioinformatic, molecular, and computational approaches, we show that inhibition of oogenic JNK prevents chemotherapy-induced oocyte apoptosis and POI as well as preserve long-term reproductive cycles and fertility. Mechanistically, JNK is activated upon chemotherapy-induced DNA damage in oocytes of primordial follicles, which further activates the transcription factor TAp63α and triggers oocyte apoptosis. we further used a breast cancer mouse model to demonstrate that JNK inhibition preserves the ovarian reserve without interfering with the anti-cancer efficacy of chemotherapy. Together, our research establishes JNK as a crucial determinant of oocyte apoptosis and POI following DNA-damaging cancer therapy, highlighting JNK as a promising target for developing ovarian protectant and preserving the ovarian reserve, fertility, and ovarian endocrine functions in young female cancer patients.
